Imidazole derivatives having an inhibitory activity for farnesyl transferase and process for preparation thereof

ABSTRACT

The present invention relates to novel imidazole derivatives which show an inhibitory activity against farnesyl transferase, pharmaceutically acceptable salts or isomers thereof and pharmaceutical compositions comprising such imidazole derivatives. More particularly, the present invention relates to intermediate compounds which are used in the preparation of the imidazole derivatives of the invention. Related processes also are disclosed.

This application is a divisional of application Ser. No. 09/554,646filed May 17, 2000 now U.S. Pat. No. 6,268,363 which is a 371 ofPCt/KR98/00377 filed Nov. 25, 1998.

TECHNICAL FIELD

The present invention relates to a novel imidazole derivativerepresented by the following formula (1) which shows an inhibitoryactivity against farnesyl transferase:

in which A, n₁ and Y are defined as described below, or pharmaceuticallyacceptable salts or isomers thereof.

The present invention also relates to a process for preparation of thecompound of formula (1), to intermediates which are used in thepreparation of the compound of formula (1), and to a pharmaceuticalcomposition comprising the compound of formula (1) as an activeingredient.

BACKGROUND ART

Mammalian Ras proteins act as molecular switches in the signallingevents associated with cell growth and differentiation. The rasproto-oncogene family consists of three members, N-, K-, and H-ras,which code for highly homologous 4 types of proteins; i.e., H, N-rasproteins of 189 residues and two isomorphic K-ras-4B and K-ras-4Aproteins, of 188 and 189 residues, respectively. The chemical basis forthe switch mechanism involves cycling of the protein between theinactive (off) guanosine diphosphate (GDP) bound state and the active(on) guanosine triphosphate (GTP) bound state (Boume, H. R.; Sanders, D.A.; McCormick. F.; Nature, 1991, 349, 117). Biochemical and structuralstudies have shown that point mutations of the residues 12, 13 and 61,positioned in the neighborhood of phosphoryl ground of GTP, resulting inthe decrease of guanosime triphosphatase activity are associated withmany human cancers, particularly, pancreatic cancer, urinary bladdercarcinoma, colon cancer, etc. (Bos, J. L., Cancer Res., 1989, 49, 4682).

Ras protein is synthesized as a cytosolic precursor that ultimatelylocalized to the cytoplasmic face of the plasma membrane after a seriesof posttranslational modification (Gibbs, J. B., Cell 1991, 65, 1).These series of biochemical modifications, by changing the electricalcharge state or spacial structure to increase the hydrophobicity allowRas protein to attach to cell membrane more easily. The first andobligatory step in the series is the addition of a farnesyl moiety tothe cysteine residue of the C-terminal CAAX motif (C, cysteine; A,usually aliphatic residue; X, any other amino acid) in a reactioncatalyzed by farnesyl protein transferase (FTase). This modification isessential for Ras function, as demonstrated by the inability of Rasmutants lacking the C-terminal cysteine to be farnesylated, to localizeto the plasma, and to transform mammalian cells in culture (Hancock, J.F., Magee, A. I., Childs, J. E., Marshall, C. J., Cell 1989, 57, 1167).The subsequent posttranslational modifications, cleavage of the AAXresidues, carboxyl methylation of the the farnesylated cysteine, andpalmitoylation of the cysteines located upstream of the CAAX motif in H-and N-ras proteins are not obligatory for Ras membrane association orcellular transforming activity. Interestingly, K-ras-4B, different fromH- and N-ras, has a multiple lysine rich region named polybasic domain,instead of having cysteine required for palmitoylation, therebyfacilitating the farnesylated ras protein to bind to anionic lipid layerof cell membrane. The inhibitors of FTase that catalyzes the obligatorymodification have therefore been suggested as anticancer agents fortumors in which Ras oncogene contributes to transformation (Buses, J. E.et al., Chemistry & Biology, 1995, 2, 787). A number of FTase inhibitorsrecently identified demonstrated potent and specific ability to blockRas farnesylation, signalling and transformation in transformed cellsand tumor cell lines both in vitro and in animal models (Kohl, N. E. et.al., Proc. Natl. Acad. Sci. USA. 1994, 91, 9141; Kohl, N. E. et al.,Nature Medicine, 1995, 1792).

However, most of the inhibitors are related to CAAX motif as Rassubstrate mimic and peptidic in nature or contain a sulfhydryl group(U.S. Pat. No. 5,141,851; Kohl, N. E. et. al., Science, 1993, 260, 1934;PCT/US95/12224, Graham et al.; Sebti, S. M. et. al., J. Biol. Chem.,1995. 270, 26802; James, G. L. et al., Science, 1993, 260, 1937; Bishop,W. R. et al., J. Biol. Chem., 1995, 270, 30611). Recently, a new type ofpeptidomimetic inhibitor imitating catalytic step of FTase has beenreported (Poulter, C. D. et al., J. Am. Chem. Soc., 1996, 118, 8761).The chemical basis of the inhibitor design relates to the reactionmechanism. This is, transferring prenyl group by the enzyme iselectrophilic displacement and the reaction requires (+) charge in atransition state.

These inhibitors previously described, however, possess limited activityand selectivity for inhibition of the oncogenic function of Rasproteins, particularly K-ras-4B, which is found to be most common inhuman cancer. Therefore, new inhibitor having the ability of effectivelyinhibiting K-ras activity is required.

With regard to the restenosis and vascular proliferative diseases, ithas been shown that inhibition of cellular ras prevents smooth muscleproliferation after vascular injury in vivo (Indolfi C. et al., NatureMed., 1995, 1(6), 541-545). This report definitively supports a role forfarnesyl transferase inhibitors in this disease, showing inhibition ofaccumulation and proliferation of vascular smooth muscle.

DISCLOSURE OF INVENTION

The present inventors have performed studies for developing a compoundhaving the structural characteristics imitating an intermediate state ofcatalytic reaction of FTase and as a result, found that imidazolederivatives according to the present invention can potently inhibit theenzyme.

Therefore, the object of the present invention is to provide animidazole derivative of formula (1) which inhibits the activity ofFTase, a process for preparation thereof, and an intermediate which canbe used effectively for the preparation of the compound of formula (1).

It is another object of the present invention to provide apharmaceutical composition comprising the compound of formula (1) as anactive ingredient.

BEST MODE FOR CARRYING OUT THE INVENTION

It is the first object of the present invention to provide an imidazolederivative represented by the following formula (1) which inhibit theactivity of farnesyl transferase:

in which

n₁ represents an integer of 1 to 4;

A represents hydrogen; straight-chain or branched C₁-C₁₀-alkyl which maybe optionally substituted by C₃-C₇-cycloalkyl or lower alkoxy;

or a radical selected from the following group:

wherein

R₁ and R₁′ independently of one another represent hydrogen, halogen,cyano, nitro, hydroxycarbonyl, aminocarbonyl, aminothiocarbonyl, loweralkoxy, phenoxy, phenyl, benzyloxy, or lower alkyl which may beoptionally substituted by C₃-C₆-cycloalkyl,

R₂ represents hydrogen or lower alkyl, or represents -E-F wherein E is—CH₂—, —C(O)— or —S(O)₂— and F is hydrogen; lower alkyl which may beoptionally substituted by phenoxy or biphenyl; lower alkoxy which may beoptionally substituted by aryl; phenyl; benzyl; benzyloxy; or aminowhich may be optionally substituted by lower alkyl, benzyl orC₅-C₆-cycloalkyl,

R₃ represents hydrogen, lower alkyl or phenyl,

R₄ represents a radical selected from the following group:

wherein

n₂ and n₃ independently of one another denote 0, 1, 2, 3 or 4,

R₅ and R₉ independently of one another represent hydrogen, lower alkyl,lower alkoxy, phenoxy, phenyl, hydroxy or halogen,

R₆ and R₈ independently of one another represent hydrogen, lower alkyl,lower alkoxy, phenoxy, phenyl, cyano, hydroxy or halogen,

R₇ represents hydrogen; lower alkyl which may be optionally substitutedby C₃-C₆-cycloalkyl; lower alkoxy; hydroxy; C₃-C₆-cycloalkyl; di(loweralkyl)amino; phenyl; phenoxy; or halogen,

R₁₀ represents hydrogen, lower alkyl or lower alkoxy,

Y represents a radical selected from the following group:

wherein

X represents O or S,

B represents hydrogen, or lower alkyl which may be optionallysubstituted by hydroxy, mercapto, lower alkoxy, lower alkylthio or aryl,

C represents hydrogen, or lower alkyl which may be optionallysubstituted by aryl; or represents a radical selected from the followinggroup:

wherein

R₁₁ and R₁₂ independently of one another represent hydrogen, loweralkyl, lower alkoxy, halogen, cyano, hydroxycarbonyl, aminocarbonyl,aminothiocarbonyl, hydroxy, phenyl or phenoxy,

R₁₃ and R₁₄ independently of one another represent hydrogen, loweralkyl, aryl or

 wherein X is defined as previously described, n₄ is an integer of 2 to4 and R₁₅ is lower alkyl,

D represents amino acid residue or lower alkyl ester of amino acidresidue; or represents a radical selected from the following group:

wherein

R₁₀ is defined as previously described,

Q represents O, S, S═O or SO₂,

Z represents O, S, S═O, SO₂, C═O or C═S, or represents CH—R₂₀ orN—R₂₀(wherein R₂₀ is hydrogen, lower alkyl or hydroxy),

n₅ denotes an integer of 1 to 3,

R₁₆ and R₁₇ independently of one another represents hydrogen; aryl;lower alkyl which may be optionally substituted by aryl or cyanoaryl; or

 wherein n₄, Q and R₁₀ are defined as previously described,

R₁₈ and R₁₉ independently of one another represents hydrogen; halogen;hydroxy; cyano; lower alkyl; lower alkoxy; alkoxyalkyl; alkylthio;hydroxycarbonyl; aminocarbonyl; aminothiocarbonyl; alkylsulfonyl;alkylthioalkyl; alkylthioalkyloxy; aryl; or oxy, thio, sulfonyl or loweralkyl substituted by aryl,

G represents a radical selected by the following group:

wherein

R₁₁ and R₁₂ are defined as previously described,

I represents lower alkoxy, or represents a radical selected from thefollowing group:

wherein

R₁₆, R₁₇ and Z are defined as previously described,

L represents a radical selected from the following group:

wherein Z and Q are defined as previously described, provided that (1)n₂ is other than 0 when R₃ is hydrogen, and (2) Y is other than

when A is

or pharmaceutically acceptable salts or isomers thereof.

Particularly, the compound according to the present invention has aquite different structure from the known inhibitors for farnesyltransferase, and furthermore it does never include the thiol moiety.

In the definitions for the substituents of the compound of formula (1),the term “lower alkyl” means a straight-chain or branched alkyl having 1to 4 carbon atoms which includes methyl, ethyl, isopropyl, isobutyl andt-butyl.

Since the compound of formula (1) according to the present invention mayhave asymmetric carbon atoms depending on the substituents, it can bepresent in the form of R or S isomer, racemate, or mixtures thereof.Thus, the present invention also includes all of these stereoisomers andtheir mixtures.

Also, the compound of formula (1) according to the present invention canform a pharmaceutically acceptable salt. Such salt includes non-toxicacid addition salt containing pharmaceutically acceptable anion, forexample a salt with inorganic acids such as hydrochloric acid, sulfuricacid, nitric acid, phosphoric acid, hydrobromic acid, hydriodic acid,etc., a salt with organic carboxylic acids such as tartaric acid, formicacid, citric acid, acetic acid, trichloroaretic acid, trofluoroaceticacid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleicacid, asparagic acid, etc., or a salt with sulfonic acids such asmethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,naphthalenesulfonic acid, etc.; base addition salt for example a saltwith pyridine or ammonia; and metal addition salt, for example, a saltwith alkali metal or alkaline earth metal such as lithium salt. Further,the present invention includes a solvate of the compound of formula (1)such as alcoholate or hydrate thereof. They can be produced byconventional conversion methods.

Among the compound of formula (1) according to the present invention,the preferred compounds include those wherein

n₁ represents an integer of 1 to 3,

A represents hydrogen; straight-chain or branched C₁-C₁₀-alkyl which maybe optionally substituted by C₃-C₇-cycloalkyl or lower alkoxy; or aradical selected from the following group:

wherein

R₁ and R₁′ independently of one another represent hydrogen, halogen,cyano, nitro, hydroxycarbonyl, aminocarbonyl, aminothiocarbonyl, loweralkoxy, phenoxy, phenyl, benzyloxy, or lower alkyl which may beoptionally substituted by C₃-C₆-cycloalkyl,

R₂ represents hydrogen or lower alkyl, or represents -E-F wherein E is—CH₂—, —C(O)— or —S(O)₂— and F is hydrogen; lower alkyl which may beoptionally substituted by phenoxy or biphenyl; lower alkoxy which may beoptionally substituted by aryl; phenyl; benzyl; benzyloxy; or aminowhich may be optionally substituted by lower alkyl, benzyl) orC₅-C₆-cycloalkyl,

R₃ represents hydrogen or lower alkyl,

R₄ represents a radical selected from the following group:

wherein

n₂ and n₃ independently of one another denote 0, 1, 2, 3 or 4,

R₅, R₆, R₈ and R₉ independently of one another represent hydrogen, loweralkyl, lower alkoxy, hydroxy or halogen,

R₇ represents hydrogen; lower alkyl which may be optionally substitutedby C₃-C₆-cycloalkyl; lower alkoxy; hydroxy; C₃-C₆-cycloalkyl; orhalogen,

R₁₀ represents hydrogen, methyl or methoxy,

Y represents a radical selected from the following group:

wherein

X represents O or S,

B represents hydrogen, or lower alkyl which may be optionallysubstituted by lower alkoxy or aryl,

C represents hydrogen, or lower alkyl which may be optionallysubstituted by aryl; or represents a radical selected from the followinggroup:

wherein

R₁₁ and R₁₂ independently of one another represent hydrogen, loweralkyl, lower alkoxy, halogen, cyano, aminocarbonyl, phenyl or phenoxy,

R₁₃ and R₁₄ independently of one another represent hydrogen, loweralkyl, aryl or

 wherein X is defined as previously described, n₄ is 2 and R₁₅ is loweralkyl,

D represents amino acid residue or lower alkyl ester of amino acidresidue; or represents a radical selected from the following group:

wherein

R₁₀ is defined as previously described,

Q represents O, S, S═O or SO₂,

Z represents O, S, S═O, SO₂ or C═O, or represents CH—R₂₀ or N—R₂₀(wherein R₂₀ is hydrogen, lower alkyl or hydroxy),

n₅ denotes an integer of 1 to 3,

R₁₆ and R₁₇ independently of one another represents hydrogen; aryl;lower alkyl which may be optionally substituted by aryl or cyanoaryl; or

wherein n₄, Q and R₁₀ are defined as previously described,

R₁₈ and R₁₉ independently of one another represents hydrogen; halogen;hydroxy; cyano; lower alkyl; lower alkoxy; alkoxyalkyl; alkylthio;hydroxycarbonyl; aminocarbonyl; aminothiocarbonyl; alkylsulfonyl;alkylthioalkyl; alkylthioalkyoxy; aryl; or oxy, thio, sulfonyl or loweralkyl substituted by aryl,

G represents a radical selected by the following group:

wherein

R₁₁ and R₁₂ are defined as previously described,

I represents lower alkoxy, or represents a radical selected from thefollowing group:

wherein

R₁₆, R₁₇ and Z are defined as previously described,

L represents a radical selected from the following group:

wherein Z and Q are defined as previously described, provided that (1)n₂ is other than 0 when R₃ is hydrogen, and (2) Y is other than

when A is

Particularly preferred compounds include those wherein Y represents

and C represents

Typical examples of the compound of formula (1) according to the presentinvention are presented in the following Table 1.

TABLE 1 COM. COM. NO. STRUCTURE NO. STRUCTURE 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

It is another object of the present invention to provide processes forpreparing the imidazole derivative of formula (1) as defined above.

According to the present invention, the imidazole derivative of formula(1) can be prepared by processes characterized in that

(a) a compound represented by the following formula (2) is reacted in asolvent in the presence of a base with a compound represented by thefollowing formula (3), then the trityl group in the product thusobtained is eliminated in the presence of trifluoroacetic acid toproduce a compound represented by the following formula (1a); or

(b) a compound represented by the following formula (4) is reacted in asolvent in the presence of a base with the compound of formula (3) toproduce a compound represented by the following formula (1b); or

(c) a compound represented by the following formula (5) is reacted in asolvent in the presence of a base with the compound of formula (3), thetrityl group in the product thus obtained is eliminated in the presenceof trifluoroacetic acid to produce a compound represented by thefollowing formula (6), and then hydrogenation reaction is carried out toproduce a compound represented by the following formula (1c); or

(d) a compound represented by the following formula (7) is hydrolyzed toproduce a compound represented by the following formula (8) which isthen reacted with a compound represented by the following formula (9) inthe presence of a coupling agent to produce a compound represented bythe following formula (1d); or

(e) the carbonyl group in a compound represented by the followingformula (1e) is converted into the thiocarbonyl group in the presence ofa sulfurizing agent to produce a compound represented by the followingformula (1f); or

(f) a compound represented by the following formula (1g) is coupled in asolvent with a compound represented by the following formula (10) toproduce a compound represented by the following formula (1h); or

(g) a compound represented by the following formula (11) is cyclized inan inert solvent to produce a compound represented by the followingformula (1i); or

(h) the amide group in the compound of formula (11) is converted intothe thioamide group to produce a compound represented by the followingformula (12) which is then cyclized in an inert solvent to produce acompound represented by the following formula (1j); or

(i) a compound represented by the following formula (13) is reacted in asolvent with a compound represented by the following formula (14a) toproduce the compound of formula (1j); or

(j) the compound of formula (13) is reacted in a solvent with a compoundrepresented by the following formula (14b) to produce a compoundrepresented by the following formula (1k); or

(k) a compound represented by the following formula (1l) is hydrolyzedin the presence of a base and the product thus obtained is reacted in asolvent in the presence of a coupling agent with a compound representedby the following formula (15) to produce a compound represented by thefollowing formula (1m); or

(l) a compound represented by the following formula (16) is reacted in asolvent in the presence of a base with a compound represented by thefollowing formula (17) to produce a compound represented by thefollowing formula (1n); or

(m) a compound represented by the following formula (18) is reacted in asolvent in the presence of a base with the compound of formula (17) anddeprotected to produce a compound represented by the following formula(1o) which is then coupled with a compound represented by the followingformula (19) to produce a compound represented by the following formula(1p):

in the above reaction schemes

A, n₁, B, C, X, D, R₁₆, R₁₇, R₂, G, I, L, E and F are defined aspreviously described,

I′ represents lower alkoxy,

I″ is identical with I except that lower alkoxy is not included,

T represents hydroxy or reactive leaving group, preferably halogen,

Tr represents trityl,

Cbz represents benzyloxycarbonyl and has the same meaning through thepresent specification.

However, the compound according to the present invention may beconveniently prepared by any methods designed by combining varioussynthetic ways known in the prior arts, and such combination can beeasily performed by a person having ordinary skill in this art. Theprocesses (a) to (m) will be more specifically explained in below.

In processes (a) to (e) for preparing the compound according to thepresent invention, any inert solvents which does not adversely affect tothe reaction, preferably one or more selected from a group consisting ofdimethylformamide, dimethylacetamide, ethanol, water, methylenechloride, chloroform, tetrahydrofuran and N-methylpyrrolidinone can beused. As the base, one or more selected from a group consisting ofsodium hydride, potassium hydroxide, potassium carbonate, potassiumt-butoxide, sodium amide, sodium bis(trimethylsilyl)amide and potassiumbis(trimethylsilyl)amide, more preferably sodium hydride or potassiumhydroxide can be mentioned. As the coupling agent used in the processfor reacting the compound of formula (8) with the compound of formula(9), a mixture of 1-hydroxybenzotrizole and one or more substancesselected from a group consisting of carbodiimides such asdicyclohexylcarbodiimide(DCC),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(EDC),1,1′-dicarbonyldiimidazole(CDI), etc., and inorganic dehydrating agentsuch as silicone tetrachloride can be mentioned. Among them, a mixtureof 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(EDC) and1-hydroxybenzotrizole hydrate is particularly preferred.

The sulfurizing agent used in preparing the compound of formula (1f)from the compound of formula (1e) includes2,4-bis(phenylthio)-1,3-dithia-2,4-diphosphatane-2,4-disulfide,Lawesson's Reagent andP₄S₁₀-2,4-bis(phenylthio)-1,3-dithia-2,4-diphosphatane-2,4-disulfide canbe used most preferably.

The compound of formula (1g) which is used as a starting material inprocess (f) can be prepared by deprotecting the corresponding compoundwhich is protected by benzyloxycarbonyl group at position-1 ofpiperidine moiety. The deprotection reaction may be carried out byapplying the conventional reaction conditions, preferably by usingPd(OH)₂/C or Pd/C in an alcohol solvent under hydrogen atmosphere. Thecompound of formula (1g) thus obtained is coupled with the compound offormula (10) in an inert solvent as mentioned above optionally in thepresence of a tertiary amine base to produce the compound of formula(1h). Alternatively, the compound of formula (1g) can be reacted in thepresence of a coupling agent as mentioned for process (d) with thecarboxylic acid derivative(T═OH) to produce the compound of formula (1h)in the form of amide.

In the cyclization reactions of (g) and (h) for preparing the compounds(1i) and (1j), any inert solvents, preferably one or more selected fromtetrahydrofuran and ethanol can be used. As the sulfurizing agent usedin the conversion procedure of amide to thioamide group in process (h),2,4-bis(phenylthio)-1,3-dithia-2,4-diphosphatane-2,4-disulfide,Lawesson's Reagent or P₄S₁₀, preferably Lawesson's Reagent can bementioned.

In processes (i) and (j) for preparing the compounds (1j) and (1k) byreacting the compound of formula (13) with the compound of formula (14a)or (14b), one or more solvents selected from ethanol and isopropylalcohol can be used. Also, ordinary inorganic base, such as for example,one or more selected from a group consisting of lithium hydroxide,sodium hydroxide and potassium hydroxide, preferably lithium hydroxidecan be used in the process (k) wherein the compound of formula (1l) ishydrolyzed and then reacted with the compound of formula (15) to producethe compound of formula (1m). As the coupling agent, those mentioned forprocess (d) can be used.

In processes (l) and (m), any inert solvents, preferably one or moreselected from dimethylformamide and dimethylacetamide are used as thesolvent, and one or more selected from a group consisting of sodiumhydride, sodium amide, sodium bis(trimethylsilyl)amide and potassiumbis(trimethylsilyl)amide are used as the base. The deprotection reactionin process (m) may be carried out under the conventional reactionconditions for deprotection, preferably in the presence of Pd/C orPd(OH)₂/C under hydrogen atmosphere. Further, the coupling agent usedfor the coupling of the compound of formula (1o) with the compound offormula (19) may be the same with those mentioned for process (d).

The compound of formula (3) used as the key intermediate in processes(a) to (c) for preparing the compound of formula (1) according to thepresent invention is itself a novel compound. Therefore, it is anotherobject of the present invention to provide the compound of formula (3).As depicted in the following Reaction Schemes 14 to 16, the compound offormula (3) can be prepared by a process characterized in that acompound represented by the following formula (20) is reacted in asolvent in the presence of a coupling agent with a compound representedby the following formula (21); the compound of formula (20) is reactedin a solvent in the presence of dimethylformamide(DMF) with thionylchloride to produce a compound represented by the following formula(20a) and then the compound of formula (20a) thus obtained is reacted ina solvent with the compound of formula (21); or a compound representedby the following formula (3a) is oxidized in a solvent to produce acompound represented by the following formula (3b).

in the above Reaction Shemes 14, 15 and 16

B, C and D are defined as previously described,

Q_(a) represents S or S═O.

In the above processes according to Reaction Scheme 14 to 16 forpreparing the compound (3), any inert solvents, preferably one or moreselected from dimethylformamide, dimethylacetamide, methylene chloride,tetrahydrofuran and 1,2-dichloroethane are used as the solvent. As thecoupling agent in Reaction Scheme 14, a mixture of 1-hydroxybenzotrizoleand one or more substances selected from a group consisting ofcarbodiimides such as dicyclohexylcarbodiimide(DCC),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(EDC), etc. can bementioned. Among them, a mixture of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(EDC) and 1-hydroxybenzotrizole hydrate is particularlypreferred. The dimethylformamide in the process of Reaction Scheme 15 isused in a catalytic amount. Also, excess metachloroperbenzoic acid ispreferably used as the oxidant in the process according to the ReactionScheme 16. However, the coupling agent, oxidant, solvent, catalyst, etc.may be appropriately selected beyond those as mentioned above as far asthe purpose of the reaction can be accomplished. And the reactionconditions including the amount of reactants, reaction temperature,reaction time, etc. can easily be determined by a person skilled in thisart depending on the specific reactants.

Since the compound of formula (8) which is used as an intermediate forpreparing the compound of formula (1d) in process (d) is also a novelcompound like the compound of formula (3), it is another object of thepresent invention to provide the intermediate compound of formula (8).It can be obtained by hydrolyzing the compound of formula (7).

On the other hand, the starting materials used in the above processescan be prepared according to the specific processes described in thefollowing Reaction Schemes 17 to 29.

First, the compound of formula (2) can be obtained through protectionand halogenation as depicted in the following Reaction Scheme 17.

The compound of formula (4) wherein A is 4-cyanobenzyl may besynthesized through protection, acetylation, coupling, deprotection andhalogenation as depicted in the following Reaction Scheme 18. Morefrequently, the compound (4) is prepared by a process wherein an aminecompound is reacted with dihydroxyacetone to produce a mercaptoimidazolederivative, which is then desulfurized and halogenated as depicted inthe following Reaction Scheme 19. J. Med. Chem., 33, 1312-1329, 1990 inwhich a similar reaction is explained in detail can be referred to forthe specific reaction conditions.

The amine compound used in the above Reaction Scheme 19 wherein Arepresents 1-(benzyloxycarbonyl)piperidine-4-ylmethyl may be synthesizedfrom 4-aminomethylpiperidine through protection, benzyloxycarbonylationand deprotection as depicted in Reaction Scheme 20.

in the above Reaction Scheme 20

CbzCl represents benzylchloroformate and has the same meaning throughthe present specification.

The compound of formula (5) may be synthesized through esterification,protection, reduction and halogenation as depicted in the followingReaction Scheme 21.

in the above Reaction Scheme 21

DIBAL represents diisobutylaluminumhydride.

Also, in the above Reaction Scheme 21, the alcohol compound obtainedbefore preparing the final chloride compound may be reduced according tothe conventional manner and then reacted with thionyl chloride toproduce the compound of formula (2) wherein n₁ is 3.

The compound of formula (20) used as a starting material in preparingthe intermediate of formula (3) may be prepared, for example, accordingto a process described in the following Reaction Scheme 22, a processstarting from 1-naphthaldehyde. Particularly, the intermediate offormula (3) wherein D is 1-naphthyl can be conveniently synthesizedaccording to the following reactions of Schemes 23 and 24.

The compound of formula (11) used as a starting material in process (g)can be prepared by coupling a hydrochloride salt of glycinate derivativewith a hydrochloride salt of 4-imidazoleacetic acid, as represented inthe following Reaction Scheme 25. As the coupling agent, those mentionedin process (d) can be used. While, the compound of formula (13) used inprocess (i) may be prepared according to the procedure described in thefollowing Reaction Scheme 26 in which the chloride derivative obtainedin the process of Reaction Scheme 19 is used as a starting material.

The compounds (14a) and (14b) used in processes (i) and () can beprepared according to the following Reaction Schemes 27 and 28,respectively. First, the compound of formula 14a can be synthesized byreacting an aldehyde derivative with methyl dichloroacetate in thepresence of potassium t-butoxide. The compound of formula (14b) whereinI is I′ can be synthesized by reacting a ketone derivative with adialkylcarbonate in the presence of sodium hydride, then by reacting theproduct thus obtained with sulfuryl chloride.

Finally, the reactant of formula (17) in processes (l) and (m) wherein Grepresents 1-naphthyl and L represents N-methyl-N-(2-methoxyethyl)aminomay be prepared from 1-naphthaldehyde according to the followingReaction Scheme 29. The other compounds (17) having differentsubstituents may also be prepared by referring to Reaction Scheme 29.

The compound of formula (1) prepared according to the processes aboveshows an inhibitory activity against farnesyl transferase, and thus canbe effectively used as an anticancer agent. Therefore, the presentinvention also provides a pharmaceutical composition comprising thenovel compound of formula (1), as defined above, or a pharmaceuticallyacceptable salt or all isomer thereof as an active ingredient togetherwith a pharmaceutically acceptable carrier. Particularly, the compoundof formula (1) can be used very effectively for treating cancer,restenosis, atherosclerosis and infections from hepatitis delta andrelated viruses.

When the active compound according to the present invention is used forclinical purpose, it is preferably administered in an amount rangingfrom 10 mg to 100 mg per kg of body weight a day. The total daily dosagemay be administered in one time or over several times. However, thespecific administration dosage for the patient can be varied with thespecific compound used, body weight of the subject patient, sex,hygienic condition, diet, time or method of administration, excretionrate, mixing ratio of the agent, severity of the disease to be treated,etc.

The compound of the present invention may be administered in the form ofinjections or oral preparations. Injections, for example, sterilizedaqueous or oily suspension for injection, can be prepared according tothe known procedure using suitable dispersing agent, wetting agent, orsuspending agent. Solvents which can be used for preparing injectionsinclude water, Ringer's fluid and NaCl solution, and also sterilizedfixing oil may be conveniently used as the solvent or suspending media.Any non-stimulative fixing oil including mono-, di-glyceride may be usedfor this purpose. Fatty acid such as oleic acid may also be used forinjections.

As the solid preparation for oral administration, capsules, tablets,pills, powders and granules, etc., preferably capsules and tablets canbe mentioned. It is also desirable for tablets and pills to beformulated into enteric-coated preparation. The solid preparations maybe prepared by mixing the active compound of formula (1) according tothe present invention with at least one carrier selected from a groupconsisting of inactive diluents such as sucrose, lactose, starch, etc.,lubricants such as magnesium stearate, disintegrating agent and bindingagent.

The present invention will be more specifically explained in thefollowing examples. However, it should be understood that the followingexamples are intended to illustrate the present invention but not in anymanner to limit the scope of the present invention. Processes forpreparing the starting substances used for obtaining the compound offormula (1) will be also explained in detail in the followingPreparations.

Preparation 1 Synthesis of1-(3,4-Methylenedioxybenzyl)-5-chloromethyl-1H-imidazole Hydrochloride

1-1) 1-(3,4-Methylenedioxybenzyl)-5-hydroxymethyl-1H-imidazole

A modified method from J. Med. Chem., 33, 1312-1329. 1990 was carriedout using dihydroxyacetone dimer and piperonylamine as startingmaterials. 1.37 g (10 mmol) of piperonylamine, 1.08 g (5.5 mmol) ofdihydroxyacetone dimer and 1.15 g (11 mmol) of potassium thiocyanidewere introduced to 10 ml of isopropyl alcohol, and then 2 ml of aceticacid was added thereto and the mixture was reacted at room temperaturefor 48 hours. The reaction mixture was filtered and the residual solidthus obtained was washed with 5 ml of isopropyl alcohol(×2) and with 5ml of water(×2). The filtered solid was introduced into 12.5 ml of 10%aqueous nitric acid solution and the resulting solution was cooled downto 0° C. After 10 mg of sodium nitrite was added portionwise to thereaction solution, the mixture was reacted at room temperature for 1hour. The aqueous solution was washed with 10 ml of ethyl acetate,basified, and then recrystallized to obtain 1.16 g (Yield 50%) of thetitle compound.

¹H NMR(CDCl₃) δ 4.45(s, 2H), 5.13(s, 2H), 5.97(s, 2H), 6.70(m, 2H), 6.78(d, 1H), 6.95(s, 1H), 7.45(s, 1H)

FAB 233 (M+H), C₁₂H₁₂N₂O₃

1-2) 1-(3,4-Methylenedioxybenzyl)-5-chloromethyl-1H-imidazolehydrochloride

233 mg (1 mmol) of the compound prepared in Preparation 1-1) wasdissolved in 3 ml of chloroform and then 355 mg (3 mmol) of thionylchloride was slowly added dropwise thereto at 0° C. After stirring for 2hours. The solvent was removed by distillation under reduced pressureand the remained hydrochloride was eliminated to obtain the titlecompound in a yield of 95%. The product thus obtained was directly usedin the next reaction without purification.

Preparation 2 Synthesis of1-(Naphthalen-1-ylmethyl)-5-chloromethyl-1H-imidazole Hydrochloride

2-1) 1-(Naphthalen-1-ylmethyl)-5-hydroxymethyl-1H-imidazole

The title compound was obtained in a yield of 65% according to the sameprocedure as Preparation 1-1) except that dihydroxyacetone dimer and(naphthalen-1-ylmethyl)amine were used as starting materials.

¹H NMR(CDCl₃) δ 4.44(s, 2H), 5.42(s, 2H), 6.78(d, 1H), 6.85(s, 1H),7.25(m, 1H), 7.35(s, 1H), 7.43(m, 2H), 7.65(d, 1H), 7.68(d, 1H), 8.02(d,1H)

FAB 239 (M+H), C₁₅N₁₄N₂O

2-2) 1-(Naphthalen-1-ylmethyl)-5-chloromethyl-1H-imidazole hydrochloride

The title compound was obtained in a yield of 90% according to the sameprocedure as Preparation 1-2) using the compound prepared in Preparation2-1). The product thus obtained was directly used in the next reactionwithout purification.

Preparation 3 Synthesis of1-((R)-α-methylbenzyl)-5-chloromethyl-1H-imidazole Hydrochloride

3-1) 1-((R)-α-methylbenzyl)-5-hydroxymethyl-1H-imidazole

The title compound was obtained in a yield of 60% according to the sameprocedure as Preparation 1-1) except that dihydroxyacetone dimer and(R)-(+)-α-methylbenzylamine were used as starting materials.

¹H NMR(CDCl₃) δ 1.73 (d, 3H), 4.28 (s, 1H), 4.43(d, 1H), 5.60(m, 1H),6.75(s, 1H), 7.04(d, 2H), 7.23(m, 3H), 7.42(s, 1H)

FAB 203 (M+H), C₁₂H₁₄N₂O

3-2) 1-((R)-α-methylbenzyl)-5-chloromethyl-1H-imidazole hydrochloride

The title compound was obtained in a yield of 90% according to the sameprocedure as Preparation 1-2) using the compound prepared in Preparation3-1). The product thus obtained was directly used in the next reactionwithout purification.

Preparation 4 Synthesis of1-((S)-α-methylbenzyl)-5-chloromethyl-1H-imidazole Hydrochloride

4-1) 1-((S)-α-methylbenzyl)-5-hydroxymethyl-1H-imidazole

The title compound was obtained in a yield of 55% according to the sameprocedure as Preparation 1-1) except that dihydroxyacetone dimer and(S)-(+)-α-methylbenzylamine were used as starting materials.

¹H NMR(CDCl₃) δ 1.73(d, 3H), 4.28(s, 1H), 4.43(d, 1H), 5.60(m, 1H),6.75(s, 1H), 7.04(d, 2H), 7.23(m, 3H), 7.42(s, 1H)

FAB 203 (M+H), C₁₂H₁₄N₂O

4-2) 1-((S)-α-methylbenzyl)-5-chloromethyl-1H-imidazole Hydrochloride

The title compound was obtained in a yield of 94% according to the sameprocedure as Preparation 1-2) using the compound prepared in Preparation4-1). The product thus obtained was directly used in the next reactionwithout purification.

Preparation 5 Synthesis of 1-Phenethyl-5chloromethyl-1H-imidazoleHydrochloride

5-1) 1-Phenethyl-5-hydroxymethyl-1H-imidazole

The title compound was obtained in a yield of 70% according to the sameprocedure as Preparation 1-1) except that dihydroxyacetone dimer andphenethylamine were used as starting materials.

¹H NMR(CDCl₃) δ 3.08(t; 2H), 4.27(t, 2H), 4.47(s, 2H), 6.89(s, 1H),7.05(d, 2H), 7.26(m, 3H), 7.44(s, 1H)

FAB 203 (M+H), C₁₂H₁₄N₂O

5-2) 1-Phenethyl-5-chloromethyl-1H-imidazole hydrochloride

The title compound was obtained in a yield of 90% according to the sameprocedure as Preparation 1-2) using the compound prepared in Preparation5-1). The product thus obtained was directly used in the next reactionwithout purification.

Preparation 6 Synthesis of3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-naphthalen-1-yl)-1H-pyrrole

6-1) 3-(Naphthalen-1-yl)-acrylic acid ethylester

22.4 g(0.10 mol) of triethylphosphonoacetate was dissolved in 500 ml ofacetonitrile and 30.4 g(0.2 mol) of1,8-diazabicyclo[5.4.0]undec-7-ene(1,5-5)(DBU) was slowly added thereto.To this solution was slowly added 15.6 g(0.10 mol) of 1-naphthaldehydedissolved in 20 ml of tetrahydrofuran and the mixture was stirred for 8hours. The organic solvent was removed by distillation under reducedpressure. The resulting residue was dissolved in ethyl acetate, washedtwice with water, dried over magnesium sulfate, concentrated and thensubjected to silica gel column chromatography (eluent: n-hexane/ethylacetate=95/5, v/v) to obtain 20.3 g(0.090 mol, Yield 90%) of the titlecompound.

¹H NMR(CDCl₃) δ 1.33(t, 3H), 4.10(q, 2H), 6.75(q, 1H), 7.50(m, 3H),7.73(d, 1H), 7.85(m, 2H), 8.10(d, 1H), 8.21(d, 1H)

FAB 227 (M+H)

6-2) 3-(Ethoxycarbonyl)-4-(naphthalen-1-yl)-1H-pyrrole

4.3 g(18.9 mmol) of 3-(naphthalen-1-yl)-acrylic acid ethylester preparedin Preparation 6-1) and 3.68 g(18.9 mmol) of tosylmethylisocyanide weredissolved in 100 ml of tetrahydrofuran. 2.55 g(22.7 mmol) of potassiumt-butoxide dissolved in 100 mg of tetrahydrofuran was slowly addedthereto and the mixture was refluxed for 30 minutes. 100 ml of water wasadded to the reaction solution to stop the reaction and the solvent wasremoved under reduced pressure. The reaction solution was extracted withdiethylether, washed with aqueous sodium chloride solution and thendried over magnesium sulfate. The solvent was removed under reducedpressure and the resulting residue was subjected to silica gel columnchromatography(eluent: ethyl acetate/n-hexane=1/3, v/v) to obtain 3.85g(14.5 mmol, Yield 77%) of the title compound.

¹H NMR(CDCl₃) δ 1.27(t, 3H), 4.07(q, 2H), 6.76(s, 1H), 7.28-7.47(m, 5H),7.59(s, 1H), 7.82(m, 2H), 9.99(s, 1H)

FAB 266 (M+H)

6-3) 3-Hydroxycarbonyl-4-(naphthalen-1-yl)-1H-pyrrole

2.64 g(10 mmol) of the compound prepared in Preparation 6-2) wasdissolved in 50 ml of 50% ethanol and 2.24 g(40 mmol) of potassiumhydroxide was added thereto. The reaction mixture was refluxed for 7hours, cooled down to room temperature, adjusted to pH 4-5, extractedwith ethyl acetate, dried over sodium sulfate. The solvent was removedunder reduced pressure to obtain 1.90 g(8.1 mmol, Yield 81%) of thetitle compound. The product thus obtained was directly used in the nextreaction without purification.

¹H NMR(CDCl₃) δ 6.60(s, 1H), 7.32-7.49(m, 5H), 7.54(s, 1H), 7.84(m, 2H),9.92(s, 1H)

FAB 238 (M+H)

6-4)3-[N-(2-Methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole

234 mg(1 mmol) of the compound prepared in Preparation 6-3) wasdissolved in 2 ml of dimethylformamide, and then 230 mg(1.2 mmol) ofEDC, 101 mg(1 mmol) of triethylamine and 162 mg(1.2 mmol) of HOBT wereadded thereto. The resulting mixture was stirred at 0° C. for 5 minutes.To the reaction solution was added 124 mg(1 mmol) ofN-(2-methoxyethyl)-N-methylamine hydrochloride, which was then stirredat room temperature for 5 hours. The solvent was removed under reducedpressure and then 10 ml of saturated potassium carbonate solution wasadded to the residue. The resulting solution was extracted with 20 ml ofethyl acetate, washed with 10 ml of 1N aqueous hydrochloric acidsolution, washed with aqueous sodium chloride solution and water, driedover sodium sulfate and concentrated to give 246 mg(0.79 mmol, Yield79%) of the title compound.

¹H NMR(CDCl₃) δ 2.46(s, 2H), 2.80-3.40(m, 8H), 3.40(s, 1H), 6.80(s, 1H),7.00(s, 1H), 7.42(m, 4H), 7.73(d, 1H), 7.81(d, 1H), 8.17(d, 1H), 10.66(s, 1H)

FAB 309 (M+H)

Preparation 7 Synthesis of3-(Morpholin-4-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole

234 mg(1 mmol) of the compound prepared in Preparation 6-3) wasdissolved in 2 ml of dimethylformamide, and then 230 mg(1.2 mmol) of EDCand 162 mg(1.2 mmol) of HOBT were added thereto. The resulting mixturewas stirred at 0° C. for 5 minutes. To the reaction solution was added87 mg(1 mmol) of morpholine, which was then stirred at room temperaturefor 5 hours. The solvent was removed under reduced pressure and then 10ml of saturated potassium carbonate solution was added to the residue.The resulting solution was extracted with ethyl acetate, washed with 10ml of 1N aqueous hydrochloric acid solution, washed with aqueous sodiumchloride solution and water, dried over sodium sulfate and concentratedto give 243 mg(0.8 mmol, Yield 80%) of the title compound.

¹H NMR(CDCl₃) δ 2.13-3.52(br, 8H), 6.54(s, 1H), 7.31-7.51(m, 5H), 7.53(s, 1H), 7.81(m, 2H), 9.93(s, 1H)

FAB 307 (M+H)

Preparation 8 Synthesis of3-(4-Methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole

The title compound was obtained in a yield of 75% according to the sameprocedure as Preparation 64) except that the compound prepared inPreparation 6-3) and 4-methylpiperazine were used.

¹H NMR(CDCl₃) δ 1.15(br, 2H), 1.87(br, 2H), 1.92(s, 3H), 2.96(br 2H),3.41(br, 2H), 6.83(s, 1H), 7.09(s, 1H), 7.36-7.42(m, 4H) 7.73(d, 1H),7.75 (d, 1H), 8.10(d, 1H), 10.52(s, 1H)

FAB (M+H): 320

Preparation 9 Synthesis of3-{N-[2-(N,N-dimethylamino)ethyl]-N-methyl}carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole

The title compound was obtained in a yield of 82% according to the sameprocedure as Preparation 6-4) except that the compound prepared inPreparation 6-3) and N,N,N′-trimethyl-ethylenediamine were used.

¹H NMR(CDCl₃) δ 1.89(br, 3H), 2.18(br, 4H), 2.44(br, 2H), 2.75(s, 1H),2.98(br, 1H), 3.36(br, 2H), 6.84(s, 1H), 7.07(s, 1H), 7.38-7.43(m, 4H),7.74 (d, 1H), 7.83(d, 1H), 8.13(b, 1H), 10.14(br, 1H)

FAB (M+H): 322

Preparation 10 Synthesis of4-(Naphthalen-1-yl)-3-(thiomorpholin-4-yl)carbonyl-1H-pyrrole

234 mg(1 mmol) of the compound prepared in Preparation 6-3) wasdissolved in 2 ml of dimethylformamide, and then 230 mg(1.2 mmol) of EDCand 162 mg(1.2 mmol) of HOBT were added thereto. The resulting mixturewas stirred at 0° C. for 5 minutes. To the reaction solution was added87 mg(1 mmol) of thiomorpholine, which was then stirred at roomtemperature for 5 hours. The solvent was removed under reduced pressureand then 10 ml of saturated potassium carbonate solution was added tothe residue. The resulting solution was extracted with ethyl acetate,washed with 10 ml of 1N aqueous hydrochloric acid solution, washed withsaturated sodium chloride solution and water, dried over sodium sulfateand concentrated to give 258 mg(0.8 mmol, Yield 80%) of the titlecompound.

¹H NMR(CDCl₃) δ 1.35 (br, 2H), 2.14 (br, 2H), 3.21(br, 2H), 3.41(br,2H), 6.91 (s, 1H), 7.21 (s, 1H), 7.31-7.51 (m, 4H), 7.80 (d, 1H), 7.87(d, 1H), 8.11(d, 1H), 10.69(s, 1H)

FAB 323 (M+H)

Preparation 11 Synthesis of3-(1,1-Dioxothiomorpholin-4-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole

323 mg(1 mmol) of the compound prepared in Preparation 10 was dissolvedin 5 ml of dichloromethane, 430 mg(1.5 mmol) of 60% 3-chloroperbenzoicacid(MCPBA) was added thereto, and then the mixture was stirred at roomtemperature for 1 hour. 3 ml of 10% sodium thiosulfite was added to themixture in order to remove the excess 3-chloroperbenzoic acid and theresulting mixture was stirred at room temperature for 30 minutes. Afteradding 10 ml of saturated potassium carbonate solution thereto, themixture was extracted with dichloromethane, washed with saturated sodiumchloride solution and water, dried over sodium sulfate and concentratedto give 264 mg(0.75 mmol, Yield 75%) of the title compound.

¹H NMR(CDCl₃) δ 1.50-2.30(br, 4H), 3.65 (br, 4H), 6.92 (s, 1H), 7.20 (s,1H), 7.32-7.54 (m, 4H), 7.81 (d, 1H), 7.88 (d, 1H), 8.12(d, 1H),10.69(s, 1H)

FAB 355 (M+H)

Preparation 12 Synthesis of3-[N-(2-methylthioethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole

234 mg(1 mmol) of the compound prepared in Preparation 6-3) wasdissolved in 2 ml of dimethylformamide, and then 230 mg(1.2 mmol) ofEDC, 101 mg(1 mmol) of triethylamine and 162 mg(1.2 mmol) of HOBT wereadded thereto. The resulting mixture was stirred at 0° C. for 5 minutes.To the reaction solution was added 140 mg(1 mmol) ofN-(2-methylthioethyl)-N-methylamine hydrochloride, which was thenstirred at room temperature for 5 hours. The solvent was removed underreduced pressure and then 10 ml of saturated potassium carbonatesolution was added to the residue. The resulting solution was extractedwith 20 ml of ethyl acetate, washed with 10 ml of 1N aqueoushydrochloric acid solution, washed with saturated sodium chloridesolution and water, dried over sodium sulfate and concentrated to give243 mg(0.75 mmol, Yield 75%) of the title compound.

¹H NMR(CDCl₃) δ 1.98 (s, 3H), 2.13 (br, 2H), 2.46 (br, 2H), 2.65 (br,1H), 2.95 (br, 1H), 3.29 (br, 1H), 6.81 (s, 1H), 7.02 (s, 1H), 7.43 (m,4H), 7.72 (d, 1H), 7.82 (d, 1H), 8.18 (d, 1H), 10.65 (s, 1H)

FAB 325 (M+H)

Preparation 13 Synthesis of3-Hydroxycarbonyl-5methyl-4-(naphthalen-1-yl)-1H-pyrrole

13-1) 3-ethoxycarbonyl-5-methyl-4-(naphthalen-1-yl)-1H-pyrrole 4.3g(18.9 mmol) of 3-(naphthalen-1-yl)-acrylic acid ethylester prepared inPreparation 6-1) and 3.95 g(18.9 mmol) of α-methyltosylmethylisocyanidedisclosed in A. M. van Leusen, et al., Tetrahedron Letter, 1975, 40,3487 were dissolved in 100 ml of tetrahydrofuran. 2.55 g(22.7 mmol) ofpotassium t-butoxide dissolved in 100 ml of tetrahydrofuran was slowlyadded thereto, which was then refluxed for 30 minutes. To the reactionsolution was added 100 ml of water to stop the reaction and the solventwas removed under reduced pressure. The residue was extracted withdiethylether, washed with saturated sodium chloride solution and driedover magnesium sulfate. The solvent was removed under reduced pressureand the residue was subjected to silica gel column chromatography usinga solvent mixture of ethyl acetate/n-hexane(1/3, v/v) as an eluent togive 3.50 g(12.5 mmol, Yield 66%) of the title compound.

FAB 280 (M+H)

13-2) 3-Hydroxycarbonyl-5-methyl-4-(naphthalen-1-yl)-1H-pyrrole

2.80 g(10 mmol) of the compound prepared in Preparation 13-1) wasdissolved in 50 ml of 50% ethanol, 2.24 g(40 mmol) of potassiumhydroxide was added thereto, and the mixture was refluxed for 7 hours.The reaction solution was cooled down to room temperature, adjusted topH 4-5, extracted with ethyl acetate and dried over sodium sulfate. Thesolvent was eliminated under reduced pressure to obtain 2.02 g(8.1 mmol,Yield 81%) of the title compound.

FAB 252 (M+H)

Preparation 14 Synthesis of5-Methyl-3-(morpholin-4-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole

248 mg(1 mmol) of the compound prepared in Preparation 13-2) wasdissolved in 2 ml of dimethylformamide, and then 230 mg(1.2 mmol) of EDCand 162 mg(1.2 mmol) of HOBT were added thereto. The resulting mixturewas stirred at 0° C. for 5 minutes. To the reaction solution was added87 mg(1 mmol) of morpholine, which was then stirred at room temperaturefor 5 hours. The solvent was removed under reduced pressure and then 10ml of saturated potassium carbonate solution was added to the residue.The resulting solution was extracted with ethyl acetate, washed with 10ml of 1N aqueous hydrochloric acid solution, washed with saturatedsodium chloride solution and water, dried over sodium sulfate andconcentrated to give 224 mg(0.7 mmol, Yield 70%) of the title compound.

¹H NMR(CDCl₃) δ 2.12 (s, 3H), 2.80-3.40 (br, 8H), 7.01 (s, 1H),7.30-7.50 (m, 4H), 7.75-7.95 (m, 3H), 10.60 (br, 1H)

FAB 321 (M+H)

EXAMPLE 1 Synthesis of3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-1-[1-(3,4-methylenedioxybenzyl)-1H-imidazol-5-ylmethyl]-4-(naphthalen-1-yl)-1H-pyrrole(1)

62 mg(0.2 mmol) of the compound prepared in Preparation 6 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 50 mg(2.2 mmol) of the compoundprepared in Preparation 1 and the whole mixture was stirred at roomtemperature for 3 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 78 mg(Yield 75%) of the title compound.

¹H NMR(CDCl₃) δ 2.40(m, 2H), 2.72(m, 1H), 2.91(s, 3H), 3.09(m, 2H),3.32(br, 1H), 4.09(br, 1H), 4.89(s, 2H), 4.95(s, 2H), 5.89(s, 2H),6.45(s, 1H), 6.62(d, 1H), 6.63(s, 1H), 6.70(d, 1H), 7.0(s, 1H), 7.16(s,1H), 7.31(t, 1H), 7.41(m, 3H), 7.66(s, 1H), 7.73(d, 1H), 7.81(d, 1H),8.03(d, 1H)

FAB (M+H) 523, C₃₁H₃₀N₄O₂

EXAMPLE 2 Synthesis of1-[1-(3,4-Methylenedioxybenzyl)-1H-imidazol-5-ylmethyl]-3-(morpholin-4-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(2)

62 mg(0.2 mmol) of the compound prepared in Preparation 7 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 50 mg(2.2 mmol) of the compoundprepared in Preparation 1 and the whole mixture was stirred at roomtemperature for 3 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 70 mg(Yield 67%) of the title compound.

¹H NMR(CDCl₃) δ 2.36(br, 2H), 3.06(br, 4H), 3.33(br, 2H), 5.23(s, 2H),5.33(s, 2H), 5.96(s, 2H), 6.65(s, 1H), 6.70-6.85(m, 3H), 7.18-7.50(m,7H), 7.79(d, 1H), 7.81(d, 1H), 7.94(d, 1H)

FAB (M+H) 521, C₃₁H₂₈N₄O₄

EXAMPLE 3 Synthesis of1-[1-(3,4-Methylenedioxybenzyl)-1H-imidazol-5-ylmethyl]-3-(4-methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(3)

64 mg (0.2 mmol) of the compound prepared in Preparation 8 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 50 mg(2.2 mmol) of the compoundprepared in Preparation 1 and the whole mixture was stirred at roomtemperature for 3 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=90/10, v/v) toobtain 73 mg(Yield 67%) of the title compound.

¹H NMR(CDCl₃) δ 2.18(s, 3H), 2.30-2.60(br, 4H), 3.10-3.30(br, 4H), 4.98(s, 2H), 5.05(s, 2H), 5.95(s, 2H), 6.44(s, 1H), 6.53(d, 1H), 6.70(d,1H), 6.73(d, 1H), 7.14(d, 1H), 7.20-7.40(m, 3H), 7.50(m, 3H), 7.81(d,1H), 7.83(d, 1H), 7.88(d, 1H)

FAB (M+H) 534, C₃₂H₃₁N₅O₃

EXAMPLE 4 Synthesis of3-{N-[2-(N,N-dimethylamino)ethyl]-N-methyl}carbamoyl-1-[1-(3,4-methylendioxybenzyl)-1H-imidazol-5-ylmethyl]-4-(naphthalen-1-yl)-1H-pyrrole(4)

64 mg(0.2 mmol) of the compound prepared in Preparation 9 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 50 mg(2.2 mmol) of the compoundprepared in Preparation 1 and the whole mixture was stirred at roomtemperature for 3 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=90/10, v/v) toobtain 78 mg(Yield 71%) of the title compound.

¹H NMR(CDCl₃) δ 1.87(m, 1H), 2.01(m, 2H), 2.14(br, 6H), 2.36(br, 2H),2.50-3.00(br, 1H), 3.29(br, 2H), 4.87(s, 2H), 4.95(s, 2H), 5.89(s, 2H),6.45 (s, 1H), 6.50(d, 1H), 6.63(d, 1H), 6.72(d, 1H), 7.00(s, 1H),7.18(s, 1H), 7.31(br, 1H), 7.35-7.47(m. 3H), 7.54(s, 1H), 7.73(d, 1H),7.81(d, 1H), 8.01(br, 1H)

FAB (M+H) 536, C₃₂H₃₃N₅O₃

EXAMPLE 5 Synthesis of3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-naphthalen-1-yl)-1-[1-naphthalen-1-ylmethyl)-1H-imidazol-5-ylmethyl]-1H-pyrrole(5)

62 mg(0.2 mmol) of the compound prepared in Preparation 6 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 58 mg(2.2 mmol) of the compoundprepared in Preparation 2 and the whole mixture was stirred at roomtemperature for 3 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 79 mg(Yield 75%) of the title compound.

¹H NMR(CDCl₃) δ 2.37(br, 2H), 2.72(br, 1H), 2.99(br, 3H), 3.00(br, 2H),3.31(br, 1H), 3.71(br, 1H), 5.06(s, 2H), 5.48(s, 2H), 6.62(d, 1H),6.91(d, 1H0, 7.03(d, 1H), 7.27(d, 2H), 7.28-7.55(m, 6H), 7.58(s, 1H),7.69(d, 1H), 7.75(d, 1H), 7.81(d, 2H), 7.87(d, 1H), 8.00(d, 1H)

FAB (M+H) 529, C₃₄H₃₂N₄O₂

EXAMPLE 6 Synthesis of3-(Morpholin-4-yl)carbonyl-4-(naphthalen-1-yl)-1-[1-naphthalen-1-ylmethyl)-1H-imidazol-5-ylmethyl]-1H-pyrrole(6)

62 mg(0.2 mmol) of the compound prepared in Preparation 7 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 58 mg(2.2 mmol) of the compoundprepared in Preparation 2 and the whole mixture was stirred at roomtemperature for 3 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 76 mg(Yield 72%) of the title compound.

¹H NMR(CDCl₃) δ 2.38(br, 2H), 3.06(br, 4H), 3.30(br, 2H), 4.99(s, 2H),5.42(s, 2H), 6.58(d, 1H), 6.80(d, 1H), 7.00(s, 1H), 7.17(d, 1H), 7.25(s,1H), 7.26-7.54(m, 6H), 7.69(d, 1H), 7.71-7.81(m, 3H), 7.85(d, 1H),7.91(d, 1H)

FAB (M+H) 527, C₃₄H₃₀N₄O₂

EXAMPLE 7 Synthesis of3-(4-Methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1-[1-(naphthalen-1-ylmethyl)-1H-imidazol-5-ylmethyl]-1H-pyrrole(7)

62 mg(0.2 mmol) of the compound prepared in Preparation 8 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 58 mg(2.2 mmol) of the compoundprepared in Preparation 2 and the whole mixture was stirred at roomtemperature for 3 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=90/10, v/v) toobtain 75 mg(Yield 69%) of the title compound.

¹H NMR(CDCl₃) δ 1.07(br, 2H), 1.77(d, 2H), 1.85(s, 3H), 2.84(br, 2H),3.27(br, 2H), 4.99(s, 2H), 5.42(s, 2H), 6.58(d, 1H), 6.80(d, 1H),7.01(d, 1H), 7.16(d, 1H), 7.25(s, 1H), 7.31-7.60(m, 6H), 7.68(d, 1H),7.69-7.83(m, 3H), 7.85(d, 1H), 7.94(d, 1H)

FAB (M+H) 540, C₃₅H₃₃N₅O

EXAMPLE 8 Synthesis of3-[N-(2-Methoxyethyl)-N-methyl]carbamoyl-1-[1-((R)-α-methylbenzyl)-1H-imidazol-5-ylmethyl]-4-(naphthalen-1-yl)-1H-pyrrole(8)

62 mg (0.2 mmol) of the compound prepared in Preparation 6 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 50 mg(2.2 mmol) of the compoundprepared in Preparation 3 and the whole mixture was stirred at roomtemperature for 3 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 70 mg(Yield 71%) of the title compound.

¹H NMR(CDCl₃) δ 1.78(d, 3H), 2.28(s, 1H), 2.40(br, 2H), 3.02(br, 3H),3.09(br, 2H), 3.32(br, 2H), 4.71(d, 2H), 4.92(d, 2H), 5.12(q, 1H),6.59(d, 1H), 7.00(m, 3H), 7.18(s, 1H), 7.20-7.39(m, 4H), 7.40-7.62(m,3H), 7.74(m, 2H), 7.82(d, 1H), 8.04(d, 1H)

FAB (M+H) 493, C₃₁H₃₂N₄O₂

EXAMPLE 8 Synthesis of1-[1-((R)-α-methylbenzyl)-1H-imidazol-5-ylmethyl]-3-(morpholin-4-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(9)

62 mg (0.2 mmol) of the compound prepared in Preparation 7 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 50 mg(2.2 mmol) of the compoundprepared in Preparation 3 and the whole mixture was stirred at roomtemperature for 3 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 71 mg(Yield 72%) of the title compound.

¹H NMR(CDCl₃) δ 1.81(d, 3H), 2.28(br, 2H), 3.06(br, 4H), 3.29(br, 2H),4.65(d, 1H), 4.96(d, 1H), 5.14(q, 1H), 6.62(d, 1H), 7.01(d, 2H), 7.04(s,1H), 7.20(s, 1H), 7.23-7.36(m, 5H), 7.39-7.50(m, 3H), 7.76(s, 1H),7.78(d, 1H), 7.84(d, 1H), 8.00(d, 1H)

FAB (M+H) 491, C₃₁H₃₀N₄O₂

EXAMPLE 10 Synthesis of1-[1-((R)-α-methylbenzyl)-1H-imidazol-5-ylmethyl]-3-(4-methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(10)

64 mg(0.2 mmol) of the compound prepared in Preparation 8 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 50 mg(2.2 mmol) of the compoundprepared in Preparation 3 and the whole mixture was stirred at roomtemperature for 3 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=90/10, v/v) toobtain 73 mg(Yield 73%) of the title compound.

¹H NMR(CDCl₃) δ 1.09(br, 2H), 1.77(d, 3H), 1.83(s, 3H), 1.70-1.90(br,2H), 2.90(br, 2H), 3.31(br, 2H), 4.73(d, 1H), 4.92(d, 1H), 5.14(q, 1H),6.60(d, 1H), 7.01(m, 3H), 7.17(s, 1H), 7.20-7.35(m, 4H), 7.45(m, 3H),7.73(m, 2H), 7.80(d, 1H), 8.00(d 1H)

FAB (M+H) 504, C₃₂H₃₃N₅O

EXAMPLE 11 Synthesis of3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-1-[1-((S)-α-methylbenzyl)-1H-imidazol-5-ylmethyl]-4-(naphthalen-1-yl)-1H-pyrrole(11)

62 mg(0.2 mmol) of the compound prepared in Preparation 6 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 50 mg(2.2 mmol) of the compoundprepared in Preparation 4 and the whole mixture was stirred at roomtemperature for 3 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 75 mg(Yield 75%) of the title compound.

¹H NMR(CDCl₃) δ 1.78(d, 3H), 2.28(s, 1H), 2.40(br, 2H), 3.02(br, 3H),3.09(br, 2H), 3.32(br, 2H), 4.72(d, 2H), 4.93(d, 2H), 5.12(q, 1H),6.59(d, 1H), 7.00(m, 3H), 7.18(s, 1H), 7.20-7.39(m, 4H), 7.40-7.62(m,3H), 7.74(m, 2H), 7.82(d, 1H), 8.04(d, 1H)

FAB (M+H) 493, C₃₁H₃₂N₄O₂

EXAMPLE 12 Synthesis of1-[1-((S)-α-methylbenzyl)-1H-imidazol-5-ylmethyl]-3-(morpholin-4-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(12)

62 mg(0.2 mmol) of the compound prepared in Preparation 7 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 50 mg(2.2 mmol) of the compoundprepared in Preparation 4 and the whole mixture was stirred at roomtemperature for 3 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 73 mg(Yield 73%) of the title compound.

¹H NMR(CDCl₃) δ 1.81(d, 3H), 2.28(br, 2H), 3.06(br, 4H), 3.29(br, 2H),4.64(d, 1H), 4.95(d, 1H), 5.14(q, 1H), 6.62(d, 1H), 7.01(d, 2H), 7.04(s,1H), 7.20(s, 1H), 7.23-7.36(m, 5H), 7.39-7.50(m, 3H), 7.76(s, 1H),7.78(d, 1H), 7.84(d, 1H), 8.00(d, 1H)

FAB (M+H) 491, C₃₁H₃₀N₄O₂

EXAMPLE 13 Synthesis of1-[1-((S)-α-methylbenzyl)-1H-imidazol-5-ylmethyl]-3-(4-methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(13)

64 mg(0.2 mmol) of the compound prepared in Preparation 8 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 50 mg(2.2 mmol) of the compoundprepared in Preparation 4 and the whole mixture was stirred at roomtemperature for 3 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=90/10, v/v) toobtain 75 mg(Yield 75%) of the title compound.

¹H NMR(CDCl₃) δ 1.09(br, 2H), 1.77(d, 3H), 1.83(s, 3H) 1.70-1.90(br,2H), 2.90(br, 2H), 3.31(br, 2H), 4.74(d, 1H), 4.93(d, 1H), 5.14(q, 1H),6.60(d, 1H), 7.01(m, 3H), 7.17(s, 1H), 7.20-7.35(m, 4H), 7.45(m, 3H),7.73(m, 2H), 7.80(d, 1H), 8.00(d, 1H)

FAB (M+H) 504, C₃₂H₃₃N₅O

EXAMPLE 14 Synthesis of3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1-[1-(phenethyl)-1H-imidazol-5-ylmethyl]-1H-pyrrole(14)

62 mg(0.2 mmol) of the compound prepared in Preparation 6 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 50 mg(2.2 mmol) of the compoundprepared in Preparation 5 and the whole mixture was stirred at roomtemperature for 3 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 77 mg(Yield 78%) of the title compound.

¹H NMR(CDCl₃) δ 2.38(br, 2H), 2.70(m, 1H0, 2.80(t, 2H), 2.90(m, 3H),3.00(br, 2H), 3.31(br, 1H), 3.41(br, 1H), 4.03(t, 2H), 4.77(s, 2H),6.66(d, 1H), 6.97(d, 1H), 7.06(d, 1H), 7.22(m, 3H), 7.30-7.60(m, 5H),7.75(d, 1H), 7.80(d, 1H), 8.04(d, 1H)

FAB (M+H) 493, C₃₁H₃₂N₄O₂

EXAMPLE 15 Synthesis of3-(Morpholin-4-yl)carbonyl-4-(naphthalen-1-yl)-1-[1-(phenethyl)-1H-imidazol-5-ylmethyl]-1H-pyrrole(15)

62 mg(0.2 mmol) of the compound prepared in Preparation 7 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 50 mg(2.2 mmol) of the compoundprepared in Preparation 5 and the whole mixture was stirred at roomtemperature for 3 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 79 mg(Yield 80%) of the title compound.

¹H NMR(CDCl₃) δ 2.28(br, 2H), 2.81(t, 2H0, 2.83(br, 4H), 3.21(br, 2H),4.07(t, 2H), 4.78(s, 2H), 6.68(d, 1H), 6.99(d, 1H), 7.10(d, 2H), 7.10(d,2H), 7.23(m, 3H), 7.30(d, 1H), 7.50(m, 3H), 7.67(s, 1H), 7.77(d, 1H),7.82(d, 1H), 8.00(d, 1H)

FAB (M+H) 491, C₃₁H₃₀N₄O₂

EXAMPLE 16 Synthesis of3-(4-Methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1-[1-(phenethyl)-1H-imidazol-5-ylmethyl)-1H-pyrrole(16)

62 mg(0.2 mmol) of the compound prepared in Preparation 8 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 50 mg(2.2 mmol) of the compoundprepared in Preparation 5 and the whole mixture was stirred at roomtemperature for 3 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=90/10, v/v) toobtain 75 mg(Yield 75%) of the title compound.

¹H NMR(CDCl₃) δ 1.06(br, 2H), 1.90-2.00(br, 2H), 2.05(s, 3H), 2.80(t,2H), 3.37(br, 4H), 4.04(t, 2H), 4.77(s, 2H), 6.69(d, 1H), 6.99(m, 2H),7.09 (d, 2H), 7.20-7.56(m, 8H), 7.78(d, 1H), 7.83(d, 1H), 8.00(d, 1H)

FAB (M+H) 504, C₃₂H₃₃N₅O

Preparation 15 Synthesis of1-(2-Methoxy)phenethyl-5-chloromethyl-1H-imidazole Hydrochloride

15-1) 1-(2-Methoxy)phenethyl-5-hydroxymethyl-1H-imidazole

The title compound was obtained in a yield of 65% according to the sameprocedure as Preparation 1-1) except that dihydroxyacetone dimer and2-methoxyphenethylamine were used as starting materials.

¹H NMR(CDCl₃) δ 3.03(t, 2H), 3.75(s, 3H), 4.16(t, 2H), 4.47(s, 2H),4.75(s, 1H), 6.74(s, 1H), 6.75-7.00(m, 3H), 7.13-7.30(m, 1H)

FAB 233 (M+H), C₁₃H₁₆N₂O₂ (M)

15-2) 1-(2-Methoxy)phenethyl-5-chloromethyl-1H-imidazole hydrochloride

The title compound was obtained in a yield of 89% according to the sameprocedure as Preparation 1-2) using the compound prepared in Preparation15-1). The product thus obtained was directly used in the next reactionwithout purification.

Preparation 16 Synthesis of1-(4-Methoxy)phenethyl-5-chloromethyl-1H-imidazole Hydrochloride

16-1) 1-(4-Methoxy)phenethyl-5-hydroxymethyl-1H-imidazole

The title compound was obtained in a yield of 60% according to the sameprocedure as Preparation 1-1) except that dihydroxyacetone dimer and4-methoxyphenethylamine were used as starting materials.

¹H NMR(CDCl₃) δ 2.91(t, 2H), 3.68(s, 3H), 4.09(t, 2H), 4.36(s, 2H),6.70(d, 2H), 6.77(s, 1H), 6.87(d, 2H), 7.13 (s, 1H)

FAB 233 (M+H), C₁₃H₁₆N₂O₂ (M)

16-2) 1-(4-Methoxy)phenethyl-5-chloromethyl-1H-imidazole hydrochloride

The title compound was obtained in a yield of 89% according to the sameprocedure as Preparation 1-2) using the compound prepared in Preparation16-1). The product thus obtained was directly used in the next reactionwithout purification.

Preparation 17 Synthesis of1-(2-Fluoro)phenethyl-5-chloromethyl-1H-imidazole Hydrochloride

17-1) 1-(2-Fluoro)phenethyl-5-hydroxymethyl-1H-imidazole

The title compound was obtained in a yield of 68% according to the sameprocedure as Preparation 1-1) except that dihydroxyacetone dimer and2-fluorophenethylamine were used as starting materials.

¹H NMR(CDCl₃) δ 3.12(t, 2H), 3.50(br, 1H), 4.23 (t, 2H), 4.52(s, 2H),6.82(s, 1H), 7.02(m, 3H), 7.20(m, 2H)

FAB 221 (M+H), C₁₂H₁₃N₂OF (M)

17-2) 1-(2-Fluoro)phenethyl-5-chloromethyl-1H-imidazole hydrochloride

The title compound was obtained in a yield of 89% according to the sameprocedure as Preparation 1-2) using the compound prepared in Preparation17-1). The product thus obtained was directly used in the next reactionwithout purification.

Preparation 18 Synthesis of1-(2-Chloro)phenethyl-5-chloromethyl-1H-imidazole Hydrochloride

18-1) 1-(2-Chloro)phenethyl-5-hydroxymethyl-1H-imidazole

The title compound was obtained in a yield of 71% according to the sameprocedure as Preparation 1-1) except that dihydroxyacetone dimer and2-chlorophenethylamine were used as starting materials.

¹H NMR(CDCl₃) δ 3.13(t, 2H), 3.34(br, 1H), 4.18 (t, 2H), 4.42(s, 2H),6.79(s, 1H), 6.94(d, 1H), 7.03-7.20(m, 3H), 7.29(d, 1H)

FAB 237 (M+H), C₁₂H₁₃N₂OCl (M)

18-2) 1-(2-Chloro)phenethyl-5-chloromethyl-1H-imidazole hydrochloride

The title compound was obtained in a yield of 89% according to the sameprocedure as Preparation 1-2) using the compound prepared in Preparation18-1). The product thus obtained was directly used in the next reactionwithout purification.

Preparation 19 Synthesis of1-(3-Chloro)phenethyl-5-chloromethyl-1H-imidazole Hydrochloride

19-1) 1-(3-Chloro)phenethyl-5-hydroxymethyl-1H-imidazole

The title compound was obtained in a yield of 72% according to the sameprocedure as Preparation 1-1) except that dihydroxyacetone dimer and3-chlorophenethylamine were used as starting materials.

¹H NMR(CDCl₃) δ 2.95(t, 2H), 3.90(br, 1H), 4.10 (t, 2H), 4.37(s, 2H),6.74(s, 1H), 6.85(m, 1H), 6.98(s, 1H), 7.10(m, 3H)

FAB 237 (M+H), C₁₂H₁₃N₂OCl(N)

19-2) 1-(3-Chloro)phenethyl-5-chloromethyl-1H-imidazole hydrochloride

The title compound was obtained in a yield of 91% according to the sameprocedure as Preparation 1-2) using the compound prepared in Preparation19-1). The product thus obtained was directly used in the next reactionwithout purification.

Preparation 20 Synthesis of1-(3-Phenyl)propyl-5chloromethyl-1H-imidazole Hydrochloride

20-1) 1-(3-Phenyl)propyl-5-hydroxymethyl-1H-imidazole

The title compound was obtained in a yield of 73% according to the sameprocedure as Preparation 1-1) except that dihydroxyacetone dimer and3-phenylpropylamine were used as starting materials.

¹H NMR(CDCl₃) δ 2.11(m, 2H), 2.61(t, 2H), 3.98(t, 2H), 4.25(br, 1H),4.53(s, 1H), 6.76(s, 1H), 7.10-7.60(m, 6H)

FAB 217 (M+H), C₁₃H₁₆N₂O (M)

20-2) 1-(3-Phenyl)propyl-5-chloromethyl-1H-imidazole hydrochloride

The title compound was obtained in a yield of 91% according to the sameprocedure as Preparation 1-2) using the compound prepared in Preparation20-1). The product thus obtained was directly used in the next reactionwithout purification.

Preparation 21 Synthesis of1-(Naphthalen-2-yl)methyl-5-chloromethyl-1H-imidazole Hydrochloride

21-1) 1-(Naphthalen-2-yl)methyl-5-hydroxymethyl-1H-imidazole

The title compound was obtained in a yield of 58% according to the sameprocedure as Preparation 1-1) except that dihydroxyacetone dimer and(naphthalen-2-yl)methylamine were used as starting materials.

¹H NMR(CDCl₃) δ 4.36(s, 2H), 5.28(s, 2H), 6.89 s, 1H), 7.17(d, 1H),7.35(m, 2H), 7.41(s, 1H), 7.50(s, 1H), 7.65(m, 1H), 7.69(m, 2H)

FAB 239 (M+H), C₁₅H₁₄N₂O (M)

21-2) 1-(Naphthalen-2-yl)methyl-5-chloromethyl-1H-imidazolehydrochloride

The title compound was obtained in a yield of 87% according to the sameprocedure as Preparation 1-2) using the compound prepared in Preparation21-1). The product thus obtained was directly used in the next reactionwithout purification.

Preparation 22 Synthesis of1-[2-(Naphthalen-1-yl)ethyl]-5-chloromethyl-1H-imidazole Hydrochloride

22-1) 1-[2-(Naphthalen-1-yl)ethyl]-5-hydroxymethyl-1H-imidazole

The title compound was obtained in a yield of 58% according to the sameprocedure as Preparation 1-1) except that dihydroxyacetone dimer and(naphthalen-1-yl)ethylamine were used as stating materials.

¹H NMR(CDCl₃) δ 3.44(t, 2H), 4.23(t, 2H), 4.38(s, 2H), 6.79(s, 1H),7.07(d, 1H), 7.17(s, 1H), 7.24(t, 1H), 7.32-7.48(m, 2H), 7.62(d, 1H),7.74(d, 1H), 7.92(d, 1H)

FAB 253 (M+H), C₁₆H₁₆N₂O (M)

22-2) 1-[2-(Naphthalen-1-yl)ethyl]-5-chloromethyl-1H-imidazolehydrochloride

The title compound was obtained in a yield of 87% according to the sameprocedure as Preparation 1-2) using the compound prepared in Preparation22-1). The product thus obtained was directly used in the next reactionwithout purification.

Preparation 23 Synthesis of1-(4-Bromo)phenethyl-5-chloromethyl-1H-imidazole Hydrochloride

23-1) 1-(4-Bromo)phenethyl-5-hydroxymethyl-1H-imidazole

The title compound was obtained in a yield of 72% according to the sameprocedure as Preparation 1-1) except that dihydroxyacetone dimer and4-bromophenethylamine were used as starting materials.

¹H NMR(CDCl₃) δ 2.94(t, 2H), 3.76(br, 1H), 4.11(t, 2H), 4.37(s, 2H),6.74(s, 1H), 6.85(d, 2H), 6.84(d, 2H), 7.12(s, 1H), 7.29(d, 2H)

FAB 281 (M+H), C₁₂H₁₃N₂OBr (M)

23-2) 1-(4-Bromo)phenethyl-5-chloromethyl-1H-imidazole hydrochloride

The title compound was obtained in a yield of 91% according to the sameprocedure as Preparation 1-2) using the compound prepared in Preparation23-1). The product thus obtained was directly used in the next reactionwithout purification.

Preparation 24 Synthesis of1-(4-Fluoro)phenethyl-5-chloromethyl-1H-imidazole Hydrochloride

24-1) 1-(4-Fluoro)phenethyl-5-hydroxymethyl-1H-imidazole

The title compound was obtained in a yield of 72% according to the sameprocedure as Preparation 1-1) except that dihydroxyacetone dimer and4-fluorophenethylamine were used as starting materials.

¹H NMR(CDCl₃) δ 2.99(t, 2H), 3.76(br, 1H), 4.15(t, 2H), 4.45(s, 2H),6.80-7.20(m, 5H), 7.26(s, 1H)

FAB 221 (M+H), C₁₂H₁₃N₂OF (M)

24-2) 1-(4-Fluoro)phenethyl-5-chloromethyl-1H-imidazole hydrochloride

The title compound was obtained in a yield of 91% according to the sameprocedure as Preparation 1-2) using the compound prepared in Preparation24-1). The product thus obtained was directly used in the next reactionwithout purification.

Preparation 25 Synthesis of1-(4-Methyl)phenethyl-5-chloromethyl-1H-imidazole Hydrochloride

25-1) 1-(4-Methyl)phenethyl-5-hydroxymethyl-1H-imidazole

The title compound was obtained in a yield of 72% according to the sameprocedure as Preparation 1-1) except that dihydroxyacetone dimer and4-methylphenethylamine were used as starting materials.

¹H NMR(CDCl₃) δ 3.02(t, 2H), 2.99(t, 2H), 3.76(br, 1H), 4.19(t, 2H),4.47(s, 2H), 6.83(s, 1H), 6.94(d, 2H), 7.06(d. 2H), 7.28(s, 1H)

FAB 217 (M+H), C₁₃H₁₆N₂O (M)

25-2) 1-(4-Methyl)phenethyl-5-chloromethyl-1H-imidazole hydrochloride

The title compound was obtained in a yield of 91% according to the sameprocedure as Preparation 1-2) using the compound prepared in Preparation25-1). The product thus obtained was directly used in the next reactionwithout purification.

Preparation 26 Synthesis of1-(4-Chloro)phenethyl-5-chloromethyl-1H-imidazole Hydrochloride

26-1) 1-(4-Chloro)phenethyl-5-hydroxymethyl-1H-imidazole

The title compound was obtained in a yield of 73% according to the sameprocedure as Preparation 1-1) except that dihydroxyacetone dimer and4-chlorophenethylamine were used as starting materials.

¹H NMR(CDCl₃) δ 3.04(t, 2H), 4.18(t, 2H), 4.48(s, 2H), 6.79(s, 1H),6.96(d, 2H), 7.20-7.40(m, 3H)

FAB 237 (M+H), C₁₂H₁₃N₂OCl (M)

26-2) 1-(4-Chloro)phenethyl-5-chloromethyl-]H-imidazole hydrochloride

The title compound was obtained in a yield of 91% according to the sameprocedure as Preparation 1-2) using the compound prepared in Preparation26-1). The product thus obtained was directly used in the next reactionwithout purification.

Preparation 27 Synthesis of1-[2-(Naphthalen-2-yl)ethyl]-5-chloromethyl-1H-imidazole Hydrochloride

27-1) 1-[2-(Naphthalen-2-yl)ethyl]-5-hydroxymethyl-1H-imidazole

The title compound was obtained in a yield of 58% according to the sameprocedure as Preparation 1-1) except that dihydroxyacetone dimer and2-(naphthalen-2-yl)ethylamine were used as starting materials.

¹H NMR(CDCl₃) δ 3.22(t, 2H), 4.28(t, 2H), 4.48(s, 2H), 6.84(s, 1H),7.19(d, 1H), 7.24(d, 2H), 7.44(m, 2H), 7.52(s, 1H), 7.76(m, 3H)

FAB 253 (M+H), C₁₆H₁₆N₂O (M)

27-2) 1-[2-(Naphthalen-2-yl)ethyl]-5-chloromethyl-1H-imidazolehydrochloride

The title compound was obtained in a yield of 88% according to the sameprocedure as Preparation 1-2) using the compound prepared in Preparation27-1). The product thus obtained was directly used in the next reactionwithout purification.

EXAMPLE 17 Synthesis of3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-1-[1-(2-methoxy)phenethyl-1H-imidazol-5-yl]methyl-4-(naphthalen-1-yl)-1H-pyrrole(17)

62 mg(0.2 mmol) of the compound prepared in Preparation 6 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 63 mg(2.2 mmol) of the compoundprepared in Preparation 15 and the whole mixture was stirred at roomtemperature for 2 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with ¹⁰me of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 78 mg(Yield 75%) of the title compound.

¹H NMR(CDCl₃) δ 2.39(s, 2H), 2.71(br, 1H), 2.90(t, 2H), 2.95-3.15(m,5H), 3.31(br, 1H), 3.52(br, 1H), 3.76(s, 3H), 4.06(t, 2H), 4.83(s, 2H),6.68(s, 1H), 6.75-6.95(m, 3H), 7.23(s, 1H), 7.25(s, 1H), 7.21(t, 1H),7.30-7.48(m, 4H), 7.50(s, 1H), 7.75(d, 1H), 7.81(d, 1H), 8.06(d, 1H)

FAB 523 (M+H), C₃₂H₃₄N₄O₃ (M)

EXAMPLE 18 Synthesis of1-[1-(2-Methoxy)phenethyl-1H-imidazol-5-yl]methyl-3-[4-methylpiperazin-1-yl]carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(18)

62 mg(0.2 mmol) of the compound prepared in Preparation 8 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 63 mg(2.2 mmol) of the compoundprepared in Preparation 15 and the whole mixture was stirred at roomtemperature for 2 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 75 mg(Yield 70%) of the title compound.

¹H NMR(CDCl₃) δ 1.09(br, 2H), 1.70-2.10(br+s, 5H), 2.85(t, 2H), 2.99(br, 2H), 3.40(br, 2H), 3.76(s, 3H), 4.04(t, 2H), 4.85(s, 2H), 6.69(d,1H), 6.80-6.92(m, 3H), 7.04(s, 1H), 7.08(s, 1H), 7.25(t, 1H), 7.30(d,1H), 7.35-7.50(m, 4H), 7.77(d, 1H), 7.80(d, 1H), 8.02(d, 1H)

FAB 534 (M+H), C₃₃H₃₄N₅O₂ (M)

EXAMPLE 19 Synthesis of3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-1-[1-(4-methoxy)phenethyl-1H-imidazol-5-yl]methyl-4-(naphthalen-1-yl)-1H-pyrrole(19)

62 mg(0.22 mmol) of the compound prepared in Preparation 6 was dissolvedin 2 mg of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 63 mg(2.2 mmol) of the compoundprepared in Preparation 16 and the whole mixture was stirred at roomtemperature for 2 hours. The solvent was removed by distillation: underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 83 mg(Yield 80%) of the title compound.

¹H NMR(CDCl₃) δ 2.38(br, 2H), 2.72(t, 2H), 2.85-3.15(m, 7H), 3.31(br,1H), 3.72(s, 3H), 3.97(t, 2H), 4.78(s, 2H), 6.69(d, 1H), 6.77 (d, 2H),6.85(d, 2H), 7.03(s, 1H), 7.06(s, 1H), 7.24-7.50(m, 5H), 7.73(d, 1H),7.82(d, 1H), 8.05(d, 1H)

FAB 523 (M+H), C₃₂H₃₄N₄O₃ (M)

EXAMPLE 20 Synthesis of1-[1-(4-Methoxy)phenethyl-1H-imidazol-5-yl]methyl-3-[4-methylpiperazin-1-yl]carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(20)

62 mg(0.2 mmol) of the compound prepared in Preparation 8 was dissolvedin 2 ml of dimethylformamide, 26.4mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 63 mg(2.2 mmol) of the compoundprepared in Preparation 16 and the whole mixture was stirred at roomtemperature for 2 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 mg of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 83mg(Yield 78%) of the title compound.

¹H NMR(CDCl₃) δ 1.05(br, 2H), 1.70-2.10(br+s, 4H), 2.24(br, 1H), 2.72(t,2H), 2.89(br, 2H), 3.30(br, 1H), 3.73(s, 3H), 3.98(t, 2H), 4.79(s, 2H),6.69(d, 1H), 6.76(d, 2H), 6.86(d, 2H), 7.08(m, 2H), 7.30-7.50(m, 5H),7.74(d, 1H), 7.80(d, 1H), 8.00(d, 1H)

FAB 534 (M+H), C₃₃H₃₅N₅O₂ (M)

EXAMPLE 21 Synthesis of1-[1-(2-Fluoro)phenethyl-1H-imidazol-5-yl]methyl-3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole(21)

62 mg(0.2 mmol) of the compound prepared in Preparation 6 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 61 mg(2.2 mmol) of the compoundprepared in Preparation 17 and the whole mixture was stirred at roomtemperature for 2 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 78 mg(Yield 77%) of the title compound.

¹H NMR(CDCl₃) δ 2.38(br, 2H), 2.70(br, 1H), 2.81(t, 2H), 2.90-3.38(m,7H), 4.03(t, 2H), 4.91(s, 2H), 6.71(d, 2H_(0, 6.92)(m, 1H), 6.95-7.12(m,4H), 7.19(m, 1H), 7.30-7.65(m, 4H), 7.73(d, 1H), 7.80(d, 1H), 8.05(d,1H)

FAB 511 (M+H), C₃₁H₃₁N₄O₂F (M)

EXAMPLE 22 Synthesis of1-[1-(2-Fluoro)phenethyl-1H-imidazol-5-yl]methyl-3-[4-methylpiperazin-1-yl]carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(22)

62 mg(0.2 mmol) of the compound prepared in Preparation 8 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 61 mg(2.2 mmol) of the compoundprepared in Preparation 17 and the whole mixture was stirred at roomtemperature for 2 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 78 mg(Yield 75%) of the title compound.

¹H NMR(CDCl₃) δ 1.04(br, 2H), 1.70-2.10(br+s, 5H), 2.81(m, 2H), 3.90(br, 2H), 3.32 (br, 2H), 4.05(t, 2H), 4.93(s, 2H), 6.72(d, 1H), 6.90(t,1H), 6.95-7.05(m, 2H), 7.10(d, 2H), 7.20(m, 1H), 7.25-7.50(m, 4H),7.75(d, 1H), 7.82(d, 2H), 8.00(d, 1H)

FAB 522 (M+H), C₃₂H₃₂N₅OF (M)

EXAMPLE 23 Synthesis of1-[1-(2-Chloro)phenethyl-1H-imidazol-5-yl]methyl-3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole(23)

62 mg(0.2 mmol) of the compound prepared in Preparation 6 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 64 mg(2.2 mmol) of the compoundprepared in Preparation 18 and the whole mixture was stirred at roomtemperature for 3 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 75 mg(Yield 71%) of the title compound.

¹H NMR(CDCl₃) δ 2.39(br, 2H), 2.71(br, 1H), 2.90-3.38(m, 9H), 4.06(t,2H), 4.87(s, 2H), 6.71(s, 1H), 6.87(m, 1H), 7.00-7.20(m, 4H),7.30-7.60(m, 6H), 7.73(d, 1H), 7.89(d, 1H), 8.06(d, 1H)

FAB 527 (M+H), C₃₁H₃₁N₄O₂Cl (M)

EXAMPLE 24 Synthesis of1-[1-(2-Chloro)phenethyl-1H-imidazol-5-yl]methyl-3-[4-methylpiperazin-1-yl]carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(24)

62 mg(0.2 mmol) of the compound prepared in Preparation 8 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 64 mg(2.2 mmol) of the compoundprepared in Preparation 18 and the whole mixture was stirred at roomtemperature for 2 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 84 mg(Yield 78%) of the title compound.

¹H NMR(CDCl₃) δ 1.04(br, 1H), 1.70-2.10(br+s, 5H), 2.35(br, 1H), 2.92(t+br, 4H), 3.32(br, 2H), 4.08(t, 2H), 4.88(s, 2H), 6.71(s, 1H), 6.87(m,1H), 7.09(m, 3H), 7.18(m, 1H), 7.30-7.55(m, 6H), 7.75(d, 1H), 7.81(d,1H), 8.01(d, 1H)

FAB 538 (M+H), C₃₂H₃₂N₅OCl (M)

EXAMPLE 25 Synthesis of1-[1-(3-Chloro)phenethyl-1H-imidazol-5-yl]methyl-3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole(25)

62 mg(0.2 mmol) of the compound prepared in Preparation 6 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 64 mg(2.2 mmol) of the compoundprepared in Preparation 19 and the whole mixture was stirred at roomtemperature for 2 hours. The solvent was removed by distillation, underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 80 mg(Yield 76%) of the title compound.

¹H NMR(CDCl₃) δ 2.37(br, 2H), 2.71(m, 3H), 2.90-3.20(m, 6H), 3.30(br,1H), 3.99(t, 2H), 4.86(s, 2H), 6.69(d, 1H), 6.81(d, 1H), 7.00(s, 1H),7.05-7.20(m, 5H), 7.30-7.50(m, 4H), 7.74(d, 1H), 7.81(d, 1H), 8.04(d,1H)

FAB 527 (M+H), C₃₁H₃₁N₄O₂Cl (M)

EXAMPLE 26 Synthesis of1-[1-(3-Chloro)phenethyl-1H-imidazol-5-yl]methyl-3-[4-methylpiperazin-1-yl]carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(26)

62 mg(0.2 mmol) of the compound prepared in Preparation 8 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 64 mg(2.2 mmol) of the compoundprepared in Preparation 19 and the whole mixture was stirred at roomtemperature for 2 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 85 mg(Yield 79%) of the title compound.

¹H NMR(CDCl₃) δ 1.05(br, 2H), 1.70-2.10(br+s, 5H), 2.69(t, 2H), 2.90(br, 2H), 3.32(br, 2H), 3.98(t, 2H), 4.87(s, 2H), 6.70(d, 1H), 6.79(d,1H), 6.98(s, 1H), 7.05-7.21(m, 3H), 7.30-7.50(m, 6H), 7.74(d, 1H),7.82(d, 1H), 7.99(d, 1H)

FAB 538 (M+H), C₃₂H₃₂N₅OCl (M)

EXAMPLE 28 Synthesis of3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1-[1-(3-phenyl)propyl-1H-imidazol-5-yl]methyl-1H-pyrrole(27)

62 mg(0.2 mmol) of the compound prepared in Preparation 6 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 62 mg(2.2 mmol) of the compoundprepared in Preparation 20 and the whole mixture was stirred at roomtemperature for 2 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water, was added to the residue. Themixture was then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 76 g(Yield 75%) of the title compound.

¹H NMR(CDCl₃) δ 1.91(m, 2H), 2.24(t, 2H), 2.56(m, 5H), 2.90-3.07(m, 4H),3.18(br, 1H), 4.03(t, 2H), 5.12(s, 2H), 6.57(s, 1H), 6.90-7.20(m, 8H),7.21-7.52(m, 3H), 7.66(d, 1H), 7.72(d, 1H), 7.89(d, 1H), 8.06(br, 1H)

FAB 507 (M+H), C₃₂H₃₄N₄O₂ (M)

EXAMPLE 28 Synthesis of3-[4-Methylpiperazin-1-yl]carbonyl-4-naphthalen-1-yl)-1-[1-(3-phenyl)propyl-1H-imidazol-5-yl]methyl-1H-pyrrole(28)

62 mg(0.2 mmol) of the compound prepared in Preparation 8 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 62 mg(2.2 mmol) of the compoundprepared in Preparation 20 and the whole mixture was stirred at roomtemperature for 2 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 77 mg(Yield 74%) of the title compound.

¹H NMR(CDCl₃) δ1.01(br, 2H), 2.80-2.01(s+br+m, 6H), 2.30(br, 1H), 2.55(t, 2H), 2.86(br, 2H), 3.30(br, 2H), 3.79(t, 2H), 5.00(s, 2H), 6.58(s,1H), 7.00-7.20(m, 8H), 7.36(m, 1H), 7.41(m, 2H), 7.50(s, 1H), 7.74(d,1H), 7.80(d, 1H), 8.00(d, 1H)

FAB 518(M+H), C₃₃H₃₅N₅O (M)

EXAMPLE 29 Synthesis of3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1-[1-(naphthalen-2-yl)methyl-1H-imidazol-5-yl]methyl-1H-pyrrole(29)

62 mg(0.2 mmol) of the compound prepared in Preparation 6 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 65 mg(2.2 mmol) of the compoundprepared in Preparation 21 and the whole mixture was stirred at roomtemperature for 2 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 85 mg(Yield 80%) of the title compound.

¹H NMR(CDCl₃) δ 2.36(br, 2H), 2.72(br, 1H), 2.98(br, 3H), 3.02(br, 2H),3.31(br, 1H), 3.73(br, 1H), 5.10(s, 2H), 5.47(s, 2H), 6.58(s, 1H),7.03(s, 1H), 7.08(d, 1H), 7.15(d, 1H), 7.21(s, 1H), 7.34-7.53(m, 7H),7.60(s, 1H), 7.70-7.83(m, 4H), 7.97(d, 1H)

FAB 529 (M+H), C₃₄H₃₀N₄O₂ (M)

EXAMPLE 30 Synthesis of3-[4-Methylpiperazin-1-yl]carbonyl-4-(naphthalen-1-yl)-1-[1-naphthalen-2-yl)methyl-1H-imidazol-5-yl]methyl-1H-pyrrole(30)

62 mg(0.2 mmol) of the compound prepared in Preparation 8 was dissolvedin 2 ml of dimethylformamide, 26.4 g(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 65 mg(2.2 mmol) of the compoundprepared in Preparation 21 and the whole mixture was stirred at roomtemperature for 2 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 74 mg(Yield 69%) of the title compound.

¹H NMR(CDCl₃) δ 0.98(br, 2H), 1.70-2.00(s+br, 5H), 2.81(br, 2H), 3.37(br, 1H), 4.88(s, 2H), 5.10(s, 2H), 6.57(s, 1H), 7.02(s, 1H), 7.08(d,1H), 7.16(d, 1H), 7.21(s, 1H), 7.34-7.52(m, 7H), 7.60(s, 1H),7.70-7.83(m, 4H), 7.97(d, 1H)

FAB 540(M+H), C₃₅H₃₃N₅O (M)

EXAMPLE 31 Synthesis of3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1-{1-[2-(naphthalen-1-yl)ethyl]-1H-imidazol-5-yl}methyl-1H-pyrrole(31)

62 mg(0.2 mmol) of the compound prepared in Preparation 6 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 68 mg(2.2 mmol) of the compoundprepared in Preparation 22 and the whole mixture was stirred at roomtemperature for 2 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 77 mg(Yield 71%) of the title compound.

¹H NMR(CDCl₃) δ 2.34(br, 2H), 2.68(br, 1H), 2.80-3.20(m, 5H), 3.23(t,2H), 3.29(br, 2H), 4.12(t, 2H), 4.45(s, 2H), 6.43(d, 1H), 6.84(d, 1H),6.97 (m, 2H), 7.21-7.52(m, 10H), 7.72(d, 1H), 7.78-7.85(m, 2H), 8.01(d,1H)

FAB 543 (M+H), C₃₅H₃₄N₄O₂ (M)

EXAMPLE 32 Synthesis of3-[4-Methylpiperazin-1-yl]carbonyl-4-(naphthalen-1-yl)-1-{1-[2-(naphthalen-1-yl)ethyl]-1H-imidazol-5-yl}methyl-1H-pyrrole(32)

62 mg(0.2 mmol) of the compound prepared in Preparation 8 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 68 mg(2.2 mmol) of the compoundprepared in Preparation 22 and the whole mixture was stirred at roomtemperature for 2 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 83 mg(Yield 75%) of the title compound.

¹H NMR(CDCl₃) δ 1.01(br, 2H), 1.70-2.00(br+s, 5H), 2.89(br, 2H), 3.27(t, 2H), 3.40(br, 2H), 4.16(t, 2H), 4.50(s, 2H), 6.45(d, 1H), 6.90(d,1H), 6.97(d, 1H), 6.99(s, 1H), 7.25-7.55(m, 8H), 7.73-7.95(m, 5H),8.00(d, 1H)

FAB 554 (M+H), C₃₆H₃₅N₅O (M)

EXAMPLE 33 Synthesis of1-[1-(4-Bromo)phenethyl-1H-imidazol-5-yl]methyl-3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole(33)

62 mg(0.2 mmol) of the compound prepared in Preparation 6 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 74 mg(2.2 mmol) of the compoundprepared in Preparation 23 and the whole mixture was stirred at roomtemperature for 2 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 88 mg(Yield 77%) of the title compound.

¹H NMR(CDCl₃) δ 2.38(br, 3H), 2.67(t, 2H), 2.90-3.23(m, 7H), 3.30(br,1H), 3.97(t, 2H), 4.88(s, 1H), 6.69(d, 1H), 6.82(d, 2H), 7.08(d, 2H),7.27-7.53(m, 7H), 7.73(d, 1H), 7.80(d, 1H), 8.02(d, 1H)

FAB 571 (M+H), C₃₁H₃₁N₄O₂Br (M)

EXAMPLE 34 Synthesis of1-[1-(4-Bromo)phenethyl-1H-imidazol-5-yl]methyl-3-[4-methylpiperazin-1-yl]carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(34)

62 mg(0.2 mmol) of the compound prepared in Preparation 8 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 74 mg(2.2 mmol) of the compoundprepared in Preparation 23 and the whole mixture was stirred at roomtemperature for 2 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 82 mg(Yield 70%) of the title compound.

¹H NMR(CDCl₃) δ 1.04(br, 2H), 1.80-2.00(br+s, 4H), 2.48(br, 1H), 2.66(t, 2H), 2.90(br, 2H), 3.31(br, 1H), 2.96(t, 2H), 4.88(s, 2H), 6.70(s,1H), 6.82(d, 2H), 7.10(d, 2H), 7.25-7.60(m, 7H), 7.75(d, 1H), 7.82(d,1H), 8.01(d, 1H)

FAB 582 (M+H), C₃₂H₃₂N₅OBr (M)

EXAMPLE 35 Synthesis of1-[1-(4-Fluoro)phenethyl-1H-imidazol-5-yl]methyl-3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole(35)

62 mg(0.2 mmol) of the compound prepared in Preparation 6 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 60 mg(2.2 mmol) of the compoundprepared in Preparation 24 and the whole mixture was stirred at roomtemperature for 2 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 77 mg(Yield 76%) of the title compound.

¹H NMR(CDCl₃) δ 2.34(br, 3H), 2.70(t, 2H), 2.90-3.20(br, 6H), 3.30(br,1H), 3.96(t, 2H), 4.86(s, 1H), 6.68(d, 1H), 6.90(m, 4H), 7.05(s, 1H),7.09(s, 1H), 7.25-7.52(m, SH), 7.73(d, 1H), 8.05(d, 1H)

FAB 511 (M+H), C₃₁H₃₁N₄O₂F (M)

EXAMPLE 36 Synthesis of1-[1-(4-Fluoro)phenethyl-1H-imidazol-5-yl]methyl-3-[4-methylpiperazin-1-yl]carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(36)

62 mg(0.2 mmol) of the compound prepared in Preparation 8 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 60 mg(2.2 mmol) of the compoundprepared in Preparation 24 and the whole mixture was stirred at roomtemperature for 2 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 78 mg(Yield 75%) of the title compound.

¹H NMR(CDCl₃) δ 1.05(br, 2H), 1.70-2.00(br+s, 4H), 2.25(br, 1H), 2.70(t, 2H), 2.90(br, 2H), 3.30(br, 2H), 3.88(t, 2H), 4.87(s, 2H), 6.69(s,1H), 6.90(m, 4H), 7.10(m, 2H), 7.29(m, 2H), 7.35-7.50(m, 3H), 7.74(d,1H), 7.82(d, 1H), 8.00(d, 1H)

FAB 522 (M+H), C₃₂H₃₂N₅OF (M)

EXAMPLE 37 Synthesis of3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-1-[1-(4-methyl)phenethyl-1H-imidazol-5-yl]methyl-4-(naphthalen-1-yl)-1H-pyrrole(37)

62 mg(0.2 mmol) of the compound prepared in Preparation 6 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 60 mg(2.2 mmol) of the compoundprepared in Preparation 25 and the whole mixture was stirred at roomtemperature for 2 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 78 mg(Yield 80%) of the title compound.

¹H NMR(CDCl₃) δ 2.02(br, 1H), 2.28(s, 3H), 2.38(br, 2H), 2.70(br, 1H),2.75(t, 2H), 2.95-3.20(m, 5H), 3.31(br, 1H), 3.99(t, 2H), 4.77(s, 2H),6.67(s, 1H), 6.85(d, 2H), 7.06(m, 4H), 7.25-7.50(m, 5H), 7.74(d, 1H),7.81(d, 1H), 8.07(d, 1H)

FAB 507 (M+H), C₃₂H₃₄N₄O₂ (M)

EXAMPLE 38 Synthesis of1-[1-(4-Methyl)phenethyl-1H-imidazol-5-yl]methyl-3-[4-methylpiperazin-1-yl]carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(38)

62 mg(0.2 mmol) of the compound prepared in Preparation 8 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 60 mg(2.2 mmol) of the compoundprepared in Preparation 25 and the whole mixture was stirred at roomtemperature for 3 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 81 mg(Yield 78%) of the title compound.

¹H NMR(CDCl₃) δ 1.07(br, 1H), 1.70-2.10(br+s, 6H), 2.28(s, 3H), 2.75(t,2H), 2.90(br, 2H), 3.33(br, 2H), 4.00(t, 2H), 4.78(s, 2H), 6.72(s, 1H),6.86(m, 2H), 7.04-7.23(m, 4H), 7.25-7.60(m, 5H), 7.75(d, 1H), 7.82(d,1H), 8.01(d, 1H)

FAB 518 (M+H), C₃₃H₃₅N₅O (M)

EXAMPLE 39 Synthesis of1-[1-(4-Chloro)phenethyl-1H-imidazol-5-yl]methyl-3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole(39)

62 mg(0.2 mmol) of the compound prepared in Preparation 6 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 64 mg(2.2 mmol) of the compoundprepared in Preparation 26 and the whole mixture was stirred at roomtemperature for 2 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 74 mg(Yield 70%) of the title compound.

¹H NMR(CDCl₃) δ 2.38(br, 2H), 2.70(t, 2H), 2.90-3.20(m, 7H), 3.30(br,1H), 3.97(t, 2H), 4.88(s, 2H), 6.69(d, 1H), 6.88(d, 2H), 7.04(s, 1H),7.09(s, 1H), 7.19(d, 1H), 7.24-7.50(m, 5H), 7.75(d, 1H), 7.81(d, 1H),8.02(d, 1H)

FAB 527 (M+H), C₃₁H₃₁N₄O₂Cl (M)

EXAMPLE 40 Synthesis of1-[1-(4-Chloro)phenethyl-1H-imidazol-5-yl]methyl]-3-[4-methylpiperazin-1-yl]carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(40)

62 mg(0.2 mmol) of the compound prepared in Preparation 8 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 64 mg(2.2 mmol) of the compoundprepared in Preparation 26 and the whole mixture was stirred at roomtemperature for 2 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 84 mg(Yield 78%) of the title compound.

1H NMR(CDCl₃) δ 1.08(br, 2H), 1.80(br, 2H), 1.95(s, 3H), 2.73(t, 2H),2.93(br, 2H), 3.35(br, 2H), 4.00(t, 2H), 4.90(s, 2H), 6.71(d, 1H),6.91(d, 2H), 7.13-7.60(m, 9H), 7.78(d, 1H), 7.82(d, 1H), 8.01(d, 1H)

FAB 538 (M+H), C₃₂H₃₂N₅OCl (M)

EXAMPLE 41 Synthesis of3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)--{1-[2-(naphthalen-2-yl)ethyl]-1H-imidazol-5-yl}methyl-1H-pyrrole(41)

62 mg(0.2 mmol) of the compound prepared in Preparation 6 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 67 mg(2.2 mmol) of the compoundprepared in Preparation 27 and the whole mixture was stirred at roomtemperature for 2 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas then extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 79 mg(Yield 71%) of the title compound.

¹H NMR(CDCl₃) δ 2.96(br, 1H), 2.39(br, 2H), 2.71(br, 1H), 2.80-3.15(m,7H), 3.32(br, 1H), 4.10(t, 2H), 4.78(s, 1H), 6.66(s, 1H), 7.09(m, 3H),7.42(m, 8H), 7.63(m, 1H), 7.75(m, 3H), 7.82(d, 1H), 8.06(d, 1H)

FAB 543 (M+H), C₃₅H₃₄N₄O₂ (M)

EXAMPLE 42 Synthesis of3-[4-Methylpiperazin-1-yl]carbonyl-4-(naphthalen-1-yl)-1-{1-[2-(naphthalen-2-yl)ethyl]-1H-imidazol-5-yl}methyl-1H-pyrrole(42)

62 mg(0.2 mmol) of the compound prepared in Preparation 8 was dissolvedin 2 ml of dimethylformamide, 26.4 mg(0.66 mmol) of sodium hydride(60%)was added thereto at 0° C. and then the mixture was stirred for 5minutes. To the mixture was added 67 mg(2.2 mmol) of the compoundprepared in Preparation 27 and the whole mixture was stirred at roomtemperature for 2 hours. The solvent was removed by distillation underreduced pressure and 3 ml of water was added to the residue. The mixturewas ten extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated, and subjected to silica gelcolumn chromatography (eluent: dichloromethane/methanol=95/5, v/v) toobtain 82 mg(Yield 74%) of the title compound.

¹H NMR(CDCl₃) δ 1.05(br, 2H), 1.70-2.00(s+br, 4H), 2.34(br, 1H), 2.90(t, 2H), 3.01(br, 2H), 3.32(br, 2H), 4.08(t, 2H), 4.78(s, 2H), 6.65(d,2H), 7.10(m, 3H), 7.21-7.42(m, 7H), 7.64(m, 1H), 7.75(m, 3H), 7.82(d,1H), 8.01(d, 1H)

FAB 554 (M+H), C₃₆H₃₅N₅O (M)

EXAMPLE 43 Synthesis of1-[1-(4-Hydroxy)phenethyl-1H-imidazol-5-yl]methyl-3-1[methylpiperazin-1-yl]carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(43)

53 mg(0.1 mmol) of the compound prepared in Example 20 was dissolved in1 ml of dichloromethane, 75 mg(0.3 mmol) of borontribromide (BBr₃) wasadded thereto, and the mixture was stirred for 3 hours. 1 ml of methanolwas added to stop the reaction and the solvent was removed bydistillation under reduced pressure. The residue was subjected to silicagel column chromatography(eluent: dichloromethane/methanol=20/80, v/v)to obtain 26 mg(Yield 50%) of tie title compound.

¹H NMR(CDCl₃) δ 1.20(br, 2H), 1.80-2.05(br+s, 4H), 2.65(t, 2H),3.00-3.60(br, 5H), 3.98(t, 2H), 4.88(s, 2H), 6.72(m, 5H), 7.09(s, 1H),7.14(d, 1H), 7.23(s, 1H), 7.27(s, 1H), 7.33(d, 1H), 7.40-7.53(m, 3H),7.77(d, 1H), 7.82(d, 1H), 7.93(d, 1H)

FAB 520 (M+H), C₃₂H₃₃O₂N₅ (M)

Preparation 28 Synthesis of 4-Chloromethyl-1-trityl-1H-imidazoleHydrochloride

28-1) 4-Hydroxymethyl-1-trityl-1H-imidazole

3.99 g(29.6 mmol) of hydroxymethylimidazole hydrochloride was dissolvedin a mixture of 30 ml of dimethylformamide and 10 ml triethylamine, andthen a solution of 9.35 g(33.5 mmol) of triphenylmethyl chloride in 110ml of dimethylformamide was added slowly thereto. After 2 hours, 500 mlof ice water was added to the reaction mixture to obtain a solid. Thissolid was recrystallized from dioxane to give 8.82 g(Yield 87%) of thetitle compound.

m.p.: 227-229° C.

28-2) 4-Chloromethyl-1-trityl-1H-imidazole hydrochloride

1.50 g(4.41 mmol) of the compound prepared in Preparation 28-1) wasdissolved in 50 ml of chloroform, 0.94 ml(13.2 mmol) of thionyl chloridewas slowly added thereto at 0° C., and the mixture was stirred at roomtemperature for 2 hours. The organic solvent was removed under reducedpressure to give 1.66 g(4.20 mmol, Yield 95%) of the title compound,which was directly used in the next reaction without purification.

Preparation 29 Synthesis of4-(5-Chloromethyl-1H-imidazol-1-ylmethyl)Benzonitrile Hydrochloride

29-1) 4-Acetoxymethyl-1-trityl-1H-imidazole

To 100 ml of pyridine were added 5.00 g(14.7 mmol) of the compoundprepared in Preparation 28-1) and 1.65 g(16.2 mmol) of acetic anhydride,and the mixture was stirred at room temperature for 24 hours. Thereaction solution was distilled under reduced pressure to remove thepyridine and then the residue was dissolved in 200 ml of ethyl acetateand washed with 100 ml of aqueous sodium chloride solution. The organicsolvent was eliminated by distillation under reduced pressure and theresidue was subjected to column chromatography (eluent:dichloromethane/methanol=20/1, v/v) to give 5.22 g(13.7 mmol, Yield 93%)of the title compound.

¹H NMR(CDCl₃) δ 2.01(s, 3H), 4.95(s, 2H), 6.88(s, 1H), 7.08(s, 5H),7.27(s, 10H), 7.45 (s, 1H)

29-2) 4-(4-Acetoxymethyl1-trityl-1H-imidazol-3-ylmethyl)benzonitrilebromide

5.00 g (13.1 mmol) of the compound prepared in Preparation 29-1) wasdissolved in 20 ml of dichloromethane, 2.82 g(14.4 mmol) of4-cyanobenzyl bromide was added thereto, and the mixture was stirred atroom temperature for 60 hours. The organic solvent was removed bydistillation under reduced pressure and the residue was subjected tocolumn chromatography(eluent: dichloromethane/methanol=5/1, v/v) to give5.31 g(9.17 mmol, Yield 70%) of the title compound.

¹H NMR(CDCl₃+CD₂OD) δ 1.95(s, 3H), 4.95(s, 2H), 5.45(s, 2H),7.11-7.40(m, 18H), 7.65(d, 2H), 8.21(s, 1H)

29-3) 4-(5-Acetoxymethyl-1H-imidazol-1-ylmethyl)benzonitrile

9.10 g(15.7 mmol) of the compound prepared in Preparation 29-2) wasdissolved in 500 ml of dichloromethane, 6.06 ml(78.7 mmol) oftrifluoroacetic acid and 12.5 ml(78.7 mmol) of triethylsilane wereslowly added thereto at 0° C., and the mixture was stirred at roomtemperature for 1 hour. The organic solvent was removed by distillationunder reduced pressure, and then the residue was adjusted to pH 10 withsaturated K₂CO₃ aqueous solution and extracted with 300 ml of ethylacetate. The organic solvent was removed by distillation under reducedpressure and the residue was subjected to column chromatography usingethyl acetate as an eluent to give 3.60 g(14.1 mmol, Yield 90%) of thetitle compound.

¹H NMR(CDCl₃) δ 1.90(s, 3H), 4.97(s, 2H), 5.25(s, 2H), 7.14(d, 2H),7.21(d, 1H), 7.67(s, 1H), 7.75(d, 2H)

29-4) 4-(5-Hydroxymethyl-1H-imidazol-1-ylmethyl)benzonitrile

4.20 g(16.5 mmol) of the compound prepared in Preparation 29-3) wasdissolved in 200 ml of methanol, 4.50 g(32.9 mmol) of K₂CO₃ was addedthereto, and the mixture was stirred at room temperature for 20 minutes.The organic solvent was removed by distillation under reduced pressureat room temperature. The residue was then extracted with 300 ml of ethylacetate and the extract was subjected to column chromatography(eluent:dichloromethane/methanol=10/1, v/v) to give 3.19 g (15.0 mmol, Yield91%) of the title compound.

¹H NMR(CDCl₃+CD₃OD) δ 4.28(s, 2H), 5.18(s, 2H), 6.84(s, 1H), 7.12(d,2H), 7.42(s, 1H), 7.55(d, 2H)

29-5) 4-(5-Chloromethyl-1H-imidazol-1-ylmethyl)benzonitrilehydrochloride

3.00 g(14.1 mmol) of the compound prepared in Preparation 29-4) wasdissolved in 40 ml of chloroform, 5.02 ml(70.5 mmol) of thionyl chloridewas added slowly thereto at 0° C., and the mixture was stirred at roomtemperature for 2 hours. The organic solvent was removed under reducedpressure to obtain 3.50 g(13.1 mmol, Yield 93%) of the title compound.This compound was directly used in the next reaction withoutpurification.

Preparation 30 Synthesis of4-(3-Chloro-1-propenyl)-1-trityl-1H-imidazole

30-1) Methyl 3-(1H-imidazol-4-yl)acrylate

500 mg (3.62 mmol) of 3-(1H-imidazol-4-yl)acrylic acid was added to 20ml of methanolic HCl and the mixture was stirred at room temperature for10 hours. The solvent was removed under reduced pressure and then 30 mlof dichloromethane was added to the residue. The mixture was washedsequentially with saturated NaHCO₃ solution, aqueous sodium chloridesolution and water. The organic layer was dried over anhydrous magnesiumsulfate and concentrated to give 510 mg(3.35 mmol, Yield 93%) of thetitle compound. This compound was used directly in the next reactionwithout purification.

30-2) Methyl 3-(1-trityl-1H-imidazol-4-yl)acrylate

350 mg(2.30 mmol) of the compound prepared in Preparation 30-1) and 705mg(2.53 mmol) of triphenylmethylchloride were dissolved in 10 ml ofdimethylformamide, and 350 μl(2.53 mmol) of triethylamine was addedthereto. After 2 hours, 100 ml of ice water was added to the reactionmixture to obtain a solid. This solid was filtered, washed withdiethylether and hexane, and then dried to give 810 mg(2.05 mmol, Yield87%) of the title compound.

¹H NMR(CDCl₃) δ 3.75(s, 3H), 6.35(d, 1H), 7.05-7.50(m, 18H)

30-3) 1-(1-Trityl-1H-imidazol-4-yl)propen-3-ol

800 mg(2.03 mmol) of the compound prepared in Preparation 30-2) wasadded to 20 ml of dry dichloromethane. After the mixture was cooled downto −78° C., 6.1 ml(1M solution in hexane) of diisobutyl-aluminum hydridewas added thereto. Temperature was raised slowly to room temperature andthen 2 ml of water was added to the mixture to stop the reaction. 3 mlof 1N NaOH was added and then 2 ml of water was added, and the mixturewas filtered through cellite. The organic layer of the filtrate wasseparated and combined with the dichloromethane-extract from the aqueouslayer. The mixture was dried over anhydrous magnesium sulfate. Theorganic solvent was removed under reduced pressure and the residue wassubjected to column chromatography(eluent:dichloromethane/methanol=20/1, v/v) to give 671 mg(1.83 mmol, Yield 90%)of the title compound.

¹H NMR(CDCl₃) δ 4.25(s, 2H), 6.45(s, 2H), 6.78(s, 1H), 7.10-7.50(m, 16H)

30-4) 4-(3-Chloropropenyl)-1-trityl-1H-imidazole

650 mg(1.77 mmol) of the compound prepared in Preparation 30-3) wasadded to 10 ml of chloroform. 135 μl(1.9 mmol) of thionyl chloride wasadded thereto at 0° C. and the mixture was stirred at room temperaturefor 2 hours. The organic solvent was removed by distillation underreduced pressure and the residue was dissolved in 10 ml of ethylacetate. The solution was washed with saturated NaHCO₃ aqueous solutionand the organic solvent was distilled under reduced pressure to give 647mg(1.68 mmol, Yield 95%) of the title compound.

¹H NMR(CDCl₃) δ 4.22(d, 2H), 6.40-6.55(m, 2H), 6.81(s, 1H), 7.10-7.50(m, 16H)

Preparation 31 Synthesis of 5-Chloromethyl-1-methylimidazoleHydrochloride

31-1) 5-Hydroxymethyl-1-methylimidazole

The title compound was obtained in a yield of 32% according to theprocedure described in J. M. Dener, L-H Zhang, H. Rapoport, J. Org.Chem., 1993, 58, 1159 using dihydroxyacetone and methylaminehydrochloride as starting materials.

¹H NMR(CDCl₃) δ 3.67(s, 3H), 4.58(s, 2H), 5.37(brs, 1H), 6.76(s, 1H),7.32(s, 1H)

31-2) 5-Chloromethyl-1-methylimidazole hydrochloride

The title compound was obtained, in a yield of 95% according to the sameprocedure as Preparation 28-2) except that the compound prepared inPreparation 31-1) was used as a starting material.

Preparation 32 Synthesis of1-(4-Bromobenzyl)-5-chloromethyl-1H-imidazole Hydrochloride

32-1)-1-(4-Bromobenzyl)-5-hydroxymethyl-1H-imidazole

The title compound was obtained in a yield of 50% according to theprocedure described in J. M. Dener, L-H Zhang, H. Rapoport, J. Org.Chem., 1993, 58, 1159 using dihydroxyacetone dimer and4-bromobenzylamine hydrochloride as starting materials.

¹H NMR (CDCl₃+CD₃OD) δ 4.46(s, 2H), 5.26(s, 2H), 7.00(s, 1H), 7.07(d,2H), 7.50(d, 2H), 7.65(s, 1H)

32-2) 1-(4-Bromobenzyl)-5-chloromethyl-1H-imidazole hydrochloride

The title compound was obtained in a yield of 96% according to the sameprocedure as Preparation 28-2) except that the compound prepared inPreparation 32-1) was used as a starting material. The product thusobtained was directly used in the next reaction without purification.

Preparation 33 Synthesis of 5-Chloromethyl-1-isobutylimidazoleHydrochloride

33-1) 5-Hydroxymethyl-1-isobutylimidazole

The title compound was obtained in a yield of 45% according to the sameprocedure as Preparation 31-1) using dihydroxyacetone and isobutylaminehydrochloride as starting materials.

¹H NMR(CDCl₃) δ 0.90(d, 6H), 1.76(m, 1H), 3.62(d, 2H), 4.24(brs, 1H),4.60(s, 2H), 6.85(s, 1H), 7.45(s, 1H)

FAB (M+H): 155

33-2) 5-Chloromethyl-1-isobutylimidazole hydrochloride

The title compound was obtained in a yield of 95% according to the sameprocedure as Preparation 28-2) except that the compound prepared inPreparation 33-1) was used as a starting material.

Preparation 34 Synthesis of 5-Chloromethyl-1-cyclohexylmethylimidazoleHydrochloride

34-1) 5-Hydroxymethyl-1-cyclohexylmethylimidazole

The title compound was obtained in a yield of 45% according to the sameprocedure as Preparation 31-1) using dihydroxyacetone andcyclohexylmethylamine hydrochloride as starting materials.

¹H NMR(CDCl₃) δ 0.94(m, 2H), 1.16(m, 3H), 1.50-1.70(m, 6H), 3.65(d, 2H),4.24(brs, 1H), 4.60(s, 2H), 6.85(s, 1H), 7.45(s, 1H)

FAB (M+H): 195

34-2) 5-Chloromethyl-1-cyclohexylmethylimidazole hydrochloride

The title compound was obtained in a yield of 95% according to the sameprocedure as Preparation 28-2) except that the compound prepared inPreparation 34-1) was used as a starting material.

Preparation 35 Synthesis of 5-Chloromethyl-1-pentylimidazoleHydrochloride

35-1) 5-Hydroxymethyl-1-pentylimidazole

The title compound was obtained in a yield of 50% according to the sameprocedure as Preparation 31-1) using dihydroxyacetone and pentylaminehydrochloride as starting materials.

¹H NMR(CDCl₃) δ 0.90(t, 3H), 1.08(brs, 2H), 1.30(m, 4H), 1.45(m, 2H),3.64(t, 2H), 4.24(brs, 1H), 4.60(s, 2H), 6.84(s, 1H), 7.44(s, 1H)

FAB (M+H): 169

35-2) 5-Chloromethyl-1-pentylimidazole hydrochloride

The title compound was obtained in a yield of 90% according to the sameprocedure as Preparation 28-2) except that the compound prepared inPreparation 35-1) was used as a starting material.

Preparation 36 Synthesis of 5-Chloromethyl-1-octylimidazoleHydrochloride

36-1) 5-Hydroxymethyl-1-octylimidazole

The title compound was obtained in a yield of 52% according to the sameprocedure as Preparation 31-1) using dihydroxyacetone and octylaminehydrochloride as starting materials.

¹H NMR(CDCl₃) δ 0.88(t, 3H), 1.18(brs, 2H), 1.30(brs, 10H), 1.42(m, 2H),3.67(t, 2H), 4.23(brs, 1H), 4.60(s, 2H), 6.84(s, 1H), 7.44(s, 1H)

FAB (M+H): 211

36-2) 5-Chloromethyl-1-octylimidazole hydrochloride

The title compound was obtained in a yield of 93% according to the sameprocedure as Preparation 28-2) except that the compound prepared inPreparation 36-1) was used as a starting material.

Preparation 37 Synthesis of 5-Chloromethyl-1-decylimidazoleHydrochloride

37-1) 5-Hydroxymethyl-1-decylimidazole

The title compound was obtained in a yield of 52% according to the sameprocedure as Preparation 31-1) using dihydroxyacetone and decylaminehydrochloride as starting materials.

¹H NMR(CDCl₃) δ 0.88(t, 3H), 1.04(brs, 2H), 1.30(brs, 14H), 1.42(m, 2H),3.68(t, 2H), 4.23(brs, 1H), 4.60(s, 2H), 6.84(s, 1H), 7.44(s,

FAB (M+H): 239

37-2) 5-Chloromethyl-1-decylimidazole hydrochloride

The title compound was obtained in a yield of 93% according to the sameprocedure as Preparation 28-2) except that the compound prepared inPreparation 37-1) was used as a starting material.

Preparation 38 Synthesis of 5-Chloromethyl-1-(3-methyl)butylimidazoleHydrochloride

38-1) 5-Hydroxymethyl-1-(3-methyl)butylimidazole

The title compound was obtained in a yield of 52% according to the sameprocedure as Preparation 31-1) using dihydroxyacetone and isoamylaminehydrochloride as starting materials.

¹H NMR(CDCl₃) δ 0.90(d, 6H), 1.32(m, 2H), 1.65(m, 1H), 3.67(t, 2H),4.23(brs, 1H), 4.60(s, 2H), 6.84(s, 1H), 7.44(s, 1H)

FAB (M+H): 169

38-2) 5-Chloromethyl-1-(3-methyl)butylimidazole hydrochloride

The title compound was obtained in a yield of 93% according to the sameprocedure as Preparation 28-2) except that the compound prepared inPreparation 38-1) was used as a starting material.

Preparation 39 Synthesis of 5-Chloromethyl-1-(2-methoxy)ethylimidazoleHydrochloride

39-1) 5-Hydroxymethyl-1-(2-methoxy)ethylimidazole

The title compound was obtained in a yield of 60% according to the sameprocedure as Preparation 31-1) using dihydroxyacetone and2-methoxyethylamine hydrochloride as starting materials.

¹H NMR(CDCl₃) δ 3.38(s, 3H), 3.42(t, 2H), 3.65(t, 2H), 4.23(brs, 1H),4.60(s, 2H), 6.84(s, 1H), 7.44(s, 1H)

FAB (M+H): 157

39-2) 5-Chloromethyl-1-(2-methoxy)ethylimidazole hydrochloride

The title compound was obtained in a yield of 93% according to the sameprocedure as Preparation 28-2) except that the compound prepared inPreparation i9-1) was used as a starting material.

Preparation 40 Synthesis of 5-Chloromethyl-1-(3-methoxy)propylimidazoleHydrochloride

40-1) 5-Hydroxymethyl-1-(3-methoxy)propylimidazole

The title compound was obtained in a yield of 61% according to the sameprocedure as Preparation 31-1) using dihydroxyacetone and3-methoxypropylamine hydrochloride as starting materials.

¹H NMR(CDCl₃) δ 1.72(m, 2H), 3.32(s, 33H), 3.46(t, 2H), 3.63(t 2H),4.23(brs, 1H), 4.60(s, 2H), 6.84(s, 1H), 7.44(s, 1H)

FAB (M+H): 171

40-2) 5-Chloromethyl-1-(3-methoxy)propylimidazole hydrochloride

The title compound was obtained in a yield of 90% according to the -sameprocedure as Preparation 28-2) except that the compound prepared inPreparation 40-1) was used as a starting material.

Preparation 41 Synthesis of 5-Chloromethyl-1-(3-ethoxy)propylimidazoleHydrochloride

41-1) 5-Hydroxymethyl-1-(3-ethoxy)propylimidazole

The title compound was obtained in a yield of 61% according to the sameprocedure as Preparation 31-1) using dihydroxyacetone and3-ethoxypropylamine hydrochloride as starting materials.

¹H NMR(CDCl₃) δ 1.20(t, 3H), 1.72(m, 2H), 3.50(s, 4H), 3.63(t, 2H),4.23(brs, 1H), 4.60(s, 2H), 6.84(s, 1H), 7.44(s, 1H)

FAB (M+H): 185

41-2) 5-Chloromethyl-1-(3-ethoxy)propylimidazole hydrochloride

The title compound was obtained in a yield of 90% according to the sameprocedure as Preparation 28-2) except that the compound prepared inPreparation 41-1) was used as a starting material.

Preparation 42 Synthesis of5-Chloromethyl-1-(3-isopropoxy)propylimidazole Hydrochloride

42-1) 5-Hydroxymethyl-1-(3-isopropoxy)propylimidazole

The title compound was obtained in a yield of 61% according to the sameprocedure as Preparation 31-1) using dihydroxyacetone and3-isopropoxypropylamine hydrochloride as starting materials.

¹H NMR(CDCl₃) δ 1.15(d, 6H), 1.71(m, 2H), 3.45-3.55(m, 3H), 3.63(t, 2H),4.23(brs, 1H), 4.60(s, 2H), 6.84(s, 1H), 7.44(s, 1H)

FAB (M+H): 199

42-2) 5-Chloromethyl-1-(3-isopropoxy)propylimidazole hydrochloride

The title compound was obtained in a yield of 90% according to the sameprocedure as Preparation 28-2) except that the compound prepared inPreparation 42-1) was used as a starting material.

EXAMPLE 44 Synthesis of1-(1H-imidazol-4-yl)methyl-4-(naphthalen-1-yl)-3-(thiophen-2-yl)carbonyl-1H-pyrrole(44)

44-1) 3-(Naphthalen-1-yl)-1-(thiophen-2-yl)-prop-2-en-1-one

3.12 g(20 mmol) of 1-naphthaldehyde and 2.52 g(20 mmol) of2-acetylthiophene were dissolved in 20 ml of methanol and 800 mg(20mmol) of sodium hydroxide was slowly added thereto. The mixture wasreacted at room temperature for 8 hours and then the solid thus producedwas filtered and dried. The filtrate was adjusted to pH 4-6 using 1Nhydrochloric acid solution and extracted with ethyl acetate. The organicsolvent was removed under reduced pressure and the residue was subjectedto column chromatography(eluent: hexane/ethyl acetate=4/1, v/v) to give4.23 g(16 mmol, Yield 80%) of the title compound together with thefiltered solid.

¹H NMR(CDCl₃) δ 7.13-7.31(m, 2H), 7.55-7.70(m, 3H), 7.70(d, 1H),7.85-7.90(m, 4H), 8.28(d, 1H), 8.70(d, 1H)

44-2) 4-(Naphthalen-1-yl)-3-(thiophen-2-yl)carbonyl-1H-pyrrole

2.64 g(9.99 mmol) of the compound prepared in Example 44-1) and 2.35g(12.0 mmol) of tosylmethylisocyanide were dissolved in 30 ml oftetrahydrofuran. 1.35 g(12.0 mmol) of potassium t-butoxide was slowlyadded thereto and the mixture was refluxed for 30 minutes. The solventwas removed under reduced pressure and then 15 ml of water and 20 ml ofethyl acetate was added to the residue. The mixture was shakedthoroughly and filtered to obtain the resulting solid. This solid waswashed with diethylether and dried to give 1.97 g(6.4 mmol, Yield 65%)of the title compound.

¹H NMR(CDCl₃) δ 6.90(s, 1H), 7.12(s, 1H), 7.20-7.45(m, 4H), 7.55(s, 1H),7.61(s, 1H), 7.70-8.00(m, 4H), 11.4(s, 1H)

44-3)4-(Naphthalen-1-yl)-3-(thiophen-2-yl)carbonyl-1-(1-trityl-1H-imidazol-4-yl)methyl-1H-pyrrole

200 mg(0.99 mmol) of the compound prepared in Example 44-2) wasdissolved in 5 ml of dimethylformamide, 95 mg(4.0 mmol) of sodiumhydride(50%) was added thereto at 0° C., and the mixture was stirred for5 minutes. 391 mg(0.99 mmol) of the compound prepared in Preparation28-2) was added to the reaction solution and stirred at room temperaturefor 5 hours. The solvent was removed by distillation under reducedpressure and the residue was extracted with ethyl acetate. The extractwas dried over anhydrous magnesium sulfate, concentrated and subjectedto column chromatography(eluent: hexane/ethyl acetate=1/3, v/v) to give205 mg(0.33 mmol, Yield 33%) of the title compound.

¹H NMR(CDCl₃) δ 5.02(s, 2H), 6.75(s, 1H), 6.79(s, 1H), 6.86(t, 1H),7.10-7.52(m, 23H), 7.71(d, 1H), 7.78(d, 1H), 7.89(d, 1H)

44-4)1-(1H-Imidazol-4-yl)methyl-4-(naphthalen-1-yl)-3-(thiophen-2-yl)carbonyl-1H-pyrrole

190 mg(0.304 mmol) of the compound prepared in Example 44-3) wasdissolved in a solvent mixture of trifluoroaceticacid/dichloromethane(0.5 ml/0.5 ml) and the solution was stirred at roomtemperature for 2 hours. The organic solvent was removed under reducedpressure. The residue was dissolved in 10 ml of ethyl acetate, washedwith saturated Na₂CO₃ solution and water, dried over anhydrous magnesiumsulfate, concentrated and subjected to column chromatography(eluent:ethyl acetate) to give 103 mg(0.269 mmol, Yield 88%) of the titlecompound.

¹H NMR (CDCl₃) δ 4.87(s, 2H), 6.55(s, 1H), 6.72(s, 1H), 6.88(t, 1H),7.11-7.34(m, 7H), 7.50-7.67(m, 3H), 7.83(d, 1H)

FAB MS: 384 (M+1)

EXAMPLES 45 TO 72

The compounds represented in the following Tables 2-1 to 2-3 obtainedaccording to the similar procedure as Example 44.

TABLE 2 FAB COM. MS NO. ¹H NMR(CDCl₃) δ (M + 1) 45 4.85(s, 2H), 6.51(s,1H), 6.67(s, 1H), 7.06(s, 1H), 7.14(s, 1H), 384 7.21-7.32(m, 7H),7.61-7.74(m, 3H), 7.82(d, 1H) 46 4.95(s, 2H), 6.58(s, 1H), 6.76(s, 1H),7.13-7.35(m, 9H), 7.61- 378 7.68(m, 4H), 7.91(d, 1H) 47 4.92(s, 2H),6.61(s, 1H), 6.70(s, 1H), 7.02(d, 2H), 7.17-7.35(m, 456 9H), 7.62(d,1H), 7.70(d, 1H), 7.95(d, 1H) 48 5.03(s, 2H), 6.76(s, 1H), 6.85(s, 1H),7.07(t, 1H), 7.34-7.54(m, 456 9H), 7.72-7.79(m, 3H), 7.94(d, 1H) 495.00(s, 2N), 6.72(s, 1H), 6.77(s, 1H), 7.21-7.38(m, 11H), 7.62 456 (d,1H), 7.70(d, 1H), 7.78(4, 1H) 50 2.23(s, 3H), 5.02(s, 2H), 6.74-7.10(m,5H), 7.17-7.50(m, 8H), 392 7.65(d, 1H), 7.71(d, 1H), 7.86(d, 1H) 51(CDCl₃ + CD₃OD) 2.05(s, 3H), 5.09(s, 2H), 6.84(s, 1H), 392 6.99-7.05(m,8H), 7.23-7.36(m, 3H), 7.70(d, 1H), 7.86(d, 1H) 52 2.21(s, 3H), 4.92(s,2H), 6.62(s, 1H), 6.83(s, 1H), 7.14-735(m, 392 8H), 7.61-7.73(m, 5H),7.88(d, 1H) 53 3.66(s, 3H), 5.04(s, 2H), 6.85(s, 1H), 6.82(d, 1H),6.90(m, 1H), 408 7.12-7.17(m, 2H), 7.26-7.36(m, 8H), 7.67(t, 1H),7.74(d, 1H), 7.93(d, 1H) 54 3.75(s, 3H), 5.02(s, 2H), 6.71(m, 3H),6.80(t, 1H), 7.20-7.35(m, 408 6H), 7.60-7.75(m, 4H), 7.91(d, 1H) 554.83(s, 2H), 6.51(s, 1H), 6.63(s, 1H), 6.85(m, 1H), 412 7.03-7.29(m,10H), 7.61-7.69(m, 2H), 7.83(d, 1H) 56 5.01(s, 2H), 6.72(s, 1H), 6.77(s,1H), 7.22-7.35(m, 11H), 7.61- 412 7.80(m, 3H) 57 4.82(s, 2H), 6.63(s,1H), 6.72(s, 1H), 7.02-7.24(m, 10H), 7.56- 446 7.70(m, 3H) 58 4.91(s,2H), 6.65(s, 1H), 6.77(m, 1H), 7.20-7.31(m, 7H), 396 7.61(m, 3H),7.81(d, 1H) 59 4.92(s, 2H), 6.45(m, 1H), 6.71(m, 2H), 7.20-7.32(m, 9H),7.63- 414 7.77(m, 3H) 60 5.09(s, 2H), 6.80-7.20(m, 4H), 7.15-7.35(m,4H), 7.40(d, 1H), 403 7.45-7.50(m, 3H), 7.60(m, 1H), 7.65(d, 1H),7.75(d, 1H) 61 1.87(s, 3H), 3.55(s, 2H), 5.07(s, 2H), 6.84(s, 2H),7.08(d, 2H), 438 7.28-7.48(m, 6H), 7.57(d, 2H), 7.63(t, 1H), 7.71(d,1H), 7.90(d, 1H) 62 2.03(s, 3H), 2.74(m, 2H), 2.91(m, 2H), 5.00(s, 2H),6.67(s, 452 1H), 7.02(d, 2H), 7.14-7.43(m, 11H), 7.72-7.89(m, 3H) 631.98(s, 3H), 2.75(t, 2H), 3.90(t, 2H), 4.85(s, 2H), 6.60-6.72(m, 4684H), 7.11-7.45(m, 9H), 7.68-7.82(m, 3H) 64 2.01(s, 3H), 3.61(s, 2H),4.98(s, 2H), 6.61(s, 2H), 6.74(m, 2H), 438 7.10-7.48(m, 10H),7.71-7.88(m, 3H) 65 4.92(s, 2H), 6.62(s, 1H), 6.70(s, 1H), 7.12-7.27(m,14H), 7.53- 454 7.62(m, 4H), 7.81(d, 1H) 66 4.97(s, 2H), 6.87(d, 1H),7.15-7.46(m, 15H), 7.55-7.73(m, 4H), 454 7.86(m, 1H) 67 5.10(s, 2H),6.70(t, 2H), 6.80-6.95(m, 4H), 7.15(t, 1H), 470 7.21-7.45(m, 7H),7.50(t, 1H), 7.60(d, 2H), 7.71(d, 1H), 7.75- 7.80(m, 2H), 7.91(m, 1H) 683.82(s, 2H), 4.95(s, 2H), 6.57(s, 1H), 6.63(s, 1H), 6.92(d, 2H), 4687.04(d, 2H), 7.20-7.32(m, 10H), 7.51-7.68(m, 4H), 7.82(d, 1H) 69 4.82(s,2H), 6.41(s, 1H), 6.70(s, 1H), 6.95(s, 1H), 7.16-7.32(m, 428 9H),7.51(d, 1H), 7.59(d, 1H), 7.67(m, 3H), 7.90(d, 1H), 8.05(d, 1H) 702.38(s, 3H), 3.65(s, 3H), 4.91(s, 2H), 6.69(s, 1H), 6.97(d, 1H), 3957.00(t, 1H), 7.04(d, 1H), 7.10-7.16(m, 3H), 7.19(d, 1H), 7.34(s, 1H),7.42(s, 1H), 7.57(d, 1H), 7.67(s, 2H) 71 0.61(t, 3H), 1.02(m, 2H),1.25(m, 2H), 2.31(m, 1H), 2.47(m, 502 1H), 5.05(s, 2H), 6.57(s, 1H),6.63(s, 1H), 6.80(d, 1H), 6.87(s, 1H), 7.22-7.35(m, 7H), 7.61-7.72(m,3H) 72 3.71(d, 1H), 3.85(d, 1H), 4.85(s, 2H), 6.61(s, 1H), 6.73(d, 1H),536 6.92-7.41(m, 14H), 7.62-7.73(m, 3H)

EXAMPLE 73 Synthesis of1-[1-(4-Cyanobenzyl)-1H-imidazol-5-yl]methyl-4-(naphthalen-1-yl)-3-(thiophen-2-yl)carbonyl-1H-pyrrole(73)

80 mg(0.3 mmol) of the compound prepared in Preparation 29-5) and 90mg(0.3 mmol) of the compound prepared in Example 44-2) were dissolved in2 ml of dimethylformamide, 36 mg of sodium hydride(60%) was addedthereto, and the mixture was stirred for 2 hours. The solvent wasremoved by distillation under reduced pressure and the residue wassubjected to column chromatography(eluent:dichloromethane/methanol=10/1, v/v) to give 83 mg(0.17 mmol, Yield 56%)of the title compound

¹H NMR(CDCl₃) δ 5.02(s, 2H), 5.08(s, 1H), 6.73(s, 1H), 6.85(s, 1H),7.03(t, 1H), 7.32-7.45(m, 1H), 7.63(s, 1H), 7.75(d, 1H), 7.82(d, 1H),8.02 (d, 1H)

FAB MS: 499 (M+1)

EXAMPLES 74 77

The compounds represented in the following Table 3 were obtainedaccording to the similar procedure as Example 73.

TABLE 3 FAB COM. MS NO. ¹H NMR(CDCl₃) δ (M + 1) 74 4.82(s, 2H), 5.12(s,1H), 6.30(s, 1H), 6.41(s, 1H), 6.77-7.08(m, 499 12H), 7.31-7.46(m, 3H),7.68(d, 1H) 75 5.00(s, 2H), 5.05(s, 2H), 6.76(s, 1H), 6.82(s, 1H),7.23-7.40(m, 493 12H), 7.63(d, 2H), 7.72(d, 1H), 7.90(d, 1H) 76 5.02(s,2H), 5.08(s, 2H), 6.65(s, 1H), 6.78(s, 1H), 6.98(t, 1H), 5717.23-7.42(m, 12H), 7.65-7.73(m, 3H), 7.82(d, 1H) 77 5.03(s, 2H), 5.10(s,2H), 6.78(s, 1H), 6.87(s, 1H), 7.32-7.45(m, 571 12H), 7.74(d, 3H),7.81(d, 1H), 7.88(d, 1H)

EXAMPLE 78 Synthesis of3-(4-Fluorobenzoyl)-1-(1-methyl-1H-imidazol-4-yl)methyl-4-(naphthalen-1-yl)-1H-pyrrole(78)

The title compound was obtained in a yield of 75% according to the sameprocedure as Example 44-3) except that3-(4-fluorobenzoyl)-4-(naphthalen-1-yl)-1H-pyrrole and the compoundprepared in Preparation 31-2) were used.

¹H NMR(CDCl₃) δ 3.42(s, 3H), 5.01(s, 2H), 6.73(m, 3H), 7.11(s, 1H),7.24-7.57(m, 8H), 7.67-7.75(m, 2H)

FAB MS (M+1): 410

EXAMPLE 79 Synthesis of1-(1-Methyl-1H-imidazol-4-yl)methyl-4-(naphthalen-1-yl)-3-(4-phenoxybenzoyl)-1H-pyrrole(79)

The title compound was obtained in a yield of 70% according to the sameprocedure as Example 44-3) except that4-(naphthalen-1-yl)-3-(4-phenoxybenzoyl)-1H-pyrrole and the compoundprepared in Preparation 31-2) were used.

¹H NMR(CDCl₃) δ 3.52(s, 3H), 5.12(s, 2H), 6.63(d, 2H), 6.76(d, 1H),6.85(d, 2H), 7.12(t, 1H), 7.20(s, 1H), 7.28-7.40(m, 7H), 7.51(d, 2H),7.68(d, 2H), 7.74(d, 1H), 7.83(d, 1H)

FAB MS (M+1): 484

EXAMPLE 80 Synthesis of(S)-1-(1H-imidazol-4-yl)methyl-3-[N-(1-methoxycarbonyl-3-methylthio)propyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole(80)

80-1) Ethyl 3-(naphthalen-1-yl)acrylate

22.4 g(0.10 mol) of triethylphosphonoacetate was dissolved in 500 ml oftetrahydrofuran and 12.4 g(1.1 mol) of potassium t-butoxide was slowlyadded thereto. To this solution was slowly added 15.6 g(0.10 mol) of1-naphtaldehyde dissolved in 20 ml of tetrahydrofuran and the mixturewas stirred for 8 hours. The organic solvent was removed by distillationunder reduced pressure. The residue was dissolved in ethyl acetate,washed twice with water, dried over anhydrous magnesium sulfate,concentrated and subjected to column chromatography(eluent: hexane/ethylacetate=95/5, v/v) to give 20.3 g(0.090 mol, Yield 90%) of the titlecompound.

¹H NMR(CDCl₃) δ 1.42(t, 3H), 4.30(q, 2H), 6.50(d, 1H), 7.40-7.60(m, 3H),7.73(d, 1H), 7.82(m, 2H), 8.20(d, 1H), 8.50(d, 1H)

80-2) 3-Ethoxycarbonyl-4-(naphthalen-1-yl)-1H-pyrrole

500 mg(1.89 mmol) of ethyl 3-(naphthalen-1-yl)acrylate prepared inExample 80-1) and 368 mg(1.89 mmol) of tosylmethylisocyanide weredissolved in 10 ml of tetrahydrofuran. 255 mg(2.27 mmol) of potassiumt-butoxide dissolved in tetrahydrofuran(10 ml) was slowly added theretoand the mixture was refluxed for 30 minutes. 10 ml of water was added tothe reaction solution to stop the reaction and the solvent was removedunder reduced pressure. The residue was extracted with diethylether,washed with aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate. The solvent was removed under reduced pressure andthe residue was subjected to column chromatography(eluent: ethylacetate/hexane=1/3, v/v) to give 385 mg(1.45 mmol, Yield 77%) of thetitle compound.

¹H NMR(CDCl₃) δ 0.86(t, 3H), 4.02(q, 2H), 6.81(s, 1H), 7.48-7.61(m, 5H),7.90-7.97(m, 3H), 8.92(s, 1H)

80-3 )3-Ethoxycarbonyl-1-(1H-imidazol-4-yl)methyl-4-(naphthalen-1-yl)-1H-pyrrole

The title compound was obtained in a yield of 39% by applying theprocedure described in Examples 44-3) and 44-4) from the compoundsprepared in Example 80-2) and Preparation 28-2).

¹NMR(CDCl₃) δ 1.11(t, 3H), 4.20(q, 2H), 5.05(s, 2H), 6.78(s 1H), 6.89(s,1H), 7.38-7.49(m, 6H), 7.85-7.97(m, 3H)

80-4)3-Hydroxycarbonyl-1-(1H-imidazol-4-yl)methyl-4-(naphthalen-1-yl)-1H-pyrrole

220 mg(0.64 mmol) of the compound prepared in Example 80-3) wasdissolved in 5 ml of 50% ethanol, 216 mg(3.8 mmol) of potassiumhydroxide was added dropwise thereto, and the mixture was refluxed for 7hours. The reaction solution was cooled down to room temperature,adjusted to pH 4-5, extracted with ethyl acetate and dried overanhydrous sodium sulfate. The solvent therein was removed under reducedpressure to give 162 mg(0.51 mmol, Yield 80%) of the title compound.This compound was directly used in the next reaction withoutpurification.

¹H NMR(CD₃OD+CDCl₃) δ 5.01(s, 2H), 6.82(s, 1H), 6.87(s, 1H),7.42-7.70(m, 7H), 7.82-7.89(m, 3H)

80-5)(S)-1-(1H-Imidazol-4-yl)methyl-3-[N-(1-methoxycarbonyl-3-methylthio)propyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole

200 mg(0.60 mmol) of the compound prepared in Example 80-4) wasdissolved in 2 ml of dimethylformamide, and then 150 mg(0.78 mmol) ofEDC and 105 mg(0.78 mmol) of HOBT were added thereto. The resultingmixture was stirred at 0° C. for 5 minutes. To the reaction solution wasadded 120 mg(0.60 mmol) of L-methionine methylester, which was thenstirred at room temperature for 5 hours. The solvent was removed underreduced pressure and then 10 ml of saturated NaHCO₃ solution was addedto the residue. The resulting solution was extracted with ethyl acetate,washed with aqueous sodium chloride solution and water, dried overanhydrous sodium sulfate and concentrated. The residue was subject tocolumn chromatography(eluent: dichloromethane/methanol=20/1, v/v) togive 104 ml(0.225 mmol, Yield 37%) of the title compound.

¹H NMR(CDCl₃) δ 1.21(m, 1H), 1.55(m, 3H), 1.80(s, 3H), 3.42(s, 3H),4.43(m, 1H), 5.05(s, 2H), 5.60(d, 1H), 6.71(s, 1H), 6.95(s, 1H),7.21-7.45(m, 7H), 7.75-7.87(m, 3H)

FAB MS: 463 (M+1)

EXAMPLE 81 Synthesis of(S)-3-[N-(1-hydroxycarbonyl-3-methylthio)propyl]carbamoyl-1-(1H-imidazol-4-yl)methyl-4-(naphthalen-1-yl)-1H-pyrrole(81)

70 mg(0.15 mmol) of the compound prepared in Example 80-5) was dissolvedin 2 ml of a solvent mixture of tetrahydrofuran/methanol/water (3/2/1,v/v/v), 10 mg(0.18 mmol) of lithium hydroxide was added thereto, and themixture was stirred at room temperature for 4 hours. The solvent wasremoved under reduced pressure to give 68 mg(0.15 mmol, Yield 99.7%) ofthe lithium salt of the title compound.

¹H NMR(CD₃OD+CDCl₃) δ 1.25(m, 1H), 1.49(m, 3H), 1.85(s, 3H), 4.41 (m,1H), 5.11(s, 2H), 5.58(d, 1H), 6.70(s, 1H), 6.89(s, 1H), 7.15-7.38(m,7H), 7.76-7.81(m, 3H)

FAB MS: 449 (M+1)

EXAMPLES 82 TO 98

The compounds represented in the following Tables 4-1 and 4-2 wereobtained according to the similar procedure as Example 80.

TABLE 4 FAB COM. MS NO. ¹H NMR(CDCl₃) δ (M + 1) 82 5.02(s, 2H), 6.69(d,2H), 6.77(s, 1H), 6.92-7.18(m, 393 5H), 7.40-7.58(m, 6H), 7.75-7.87(m,4H) 83 4.06(d, 2H), 5.01(s, 2H), 5.57(t, 1H), 6.46(d, 1H), 407 6.71(s,1H), 6.83(s, 1H), 6.92-7.05(m, 3H), 7.42- 7.55(m, 7H), 7.74-7.81(m, 3H)84 0.45(brs, 2H), 1.22(brs, 4H), 2.95(brs, 2H), 3.37(brs, 385 2H),5.04(s, 2H), 6.65(s, 1H), 6.92(s, 1H), 7.08(s, 1H), 7.31-7.45(m, 6H),7.72(d, 1H), 7.82(d, 1H), 8.12 (d, 1H) 85 2.32(brs, 2H), 2.22(brs, 2H),3.23(brs, 2H), 3.65(brs, 387 2H), 5.06(s, 2H), 6.72(s, 1H), 6.95(s, 1H),7.12(s, 1H), 7.31-7.48(m, 6H), 7.81(d, 1H), 7.85(d, 1H), 8.11(d, 1H) 861.41(brs, 2H), 2.86-3.25(m, 6H), 4.97(s, 2H), 403 6.68(s, 1H), 6.85(s,1H), 7.06(s, 1H), 7.21-7.35(m, 6H), 7.72(d, 1H), 7.78(d, 1H), 7.95(d,1H) 87 2.04(brs, 4H), 3.62(brs, 4H), 5.03(s, 2H), 6.91(d, 2H), 4357.22-7.48(m, 7H), 7.81-7.88(m, 2H), 8.02(m, 1H) 88 1.46(brs, 2H),2.21(brs, 2H), 3.14(brs, 4H), 5.11(s, 386 2H), 6.88(s, 1H), 7.02(s, 1H),7.11(s, 1H), 7.32- 7.51(m, 5H), 7.62(s, 1H), 7.72-7.80(m, 2H), 8.05(d,1H) 89 (CDCl₃ + CD₃OD) 2.05(s, 3H), 3.33(brs, 8H), 5.13(s, 400 2H),6.90(s, 1H), 7.06(s, 1H), 7.21(s, 1H), 7.30- 7.55(m, 4H), 7.64(s, 1H),7.81(s, 1H), 7.88(d, 1H), 8.06(d, 1H) 90 2.62(brs, 2H), 3.15(brs, 2H),3.86(brs, 1H), 4.35(brs, 389 1H), 5.06(s, 2H), 6.83(s, 1H), 6.90(s, 1H),7.15- 7.60(m, 6H), 7.73(d, 1H), 7.82(d, 1H), 8.06(d, 1H) 91 0.22(m, 1H),0.63(m, 1H), 0.83(m, 1H), 1.24(m, 1H), 401 2.61(brs, 2H), 3.24(brs, 2H),3.65(brs, 1H), 4.94(s, 2H), 6.71(s, 1H), 6.84(s, 1H), 6.94(s, 1H), 7.24-7.42(m, 6H), 7.62-770(m, 2H), 7.94(d, 1H) 92 1.37(brs, 2H), 1.96(brs,2H), 3.52(brs, 4H), 5.21(s, 399 2H), 7.08(s, 1H), 7.20(s, 1H), 7.37(s,1H), 7.54(m, 5H), 7.70(s, 1H), 7.94(m, 2H), 8.23(d, 1H) 93 2.12(brs,2H), 3.02(brs, 2H), 4.98(s, 2H), 5.24(m, 361 1H), 6.82(s, 1H), 7.03(s,1H), 7.20-7.34(m, 6H), 7.62-7.71(m, 3H), 7.93(d, 1H) 94 2.24(brs, 2H),3.04(brs, 4H), 3.11(s, 3H), 5.03(s, 2H), 375 6.77(s, 1H), 6.89(s, 1H),7.14-7.31(m, 6H), 7.56- 7.63(m, 3H), 7.87(d, 1H) 95 2.51(m, 2H), 3.10(s,3H), 3.21(m, 2H), 3.47(s, 3H), 389 5.05(s, 2H), 6.68(s, 1H),7.05-7.48(m, 7H), 7.74- 7.85(m, 2H), 8.09(d, 1H) 96 2.58-3.50(brs, 8H),5.16(s, 2H), 6.98(d, 1H), 7.08(s, 388 1H), 7.20-7.27(m, 2H), 7.47(t,1H), 7.67(s, 1H), 7.71(t, 1H), 8.08(d, 1H), 8.15(d, 1H), 8.80(d, 1H) 973.40(m, 4H), 3.70-4.45(brs, 8H), 3.11(s, 3H), 5.18(s, 413 2H), 6.98(d,1H), 7.12(s, 1H), 7.17-7.22(m, 2H), 7.25(d, 1H), 7.30(d, 1H), 7.35(t,1H), 7.62(d, 1H), 7.90(s, 1H) 98 (CD₃OD) 3.86(s, 2H), 4.83(s, 2H),5.58(t, 1H), 432 6.37(d, 1H), 6.52(s, 2H), 6.81(s, 1H), 7.05-7.35(m,9H), 7.51(d, 1H), 7.54(d, 1H), 7.58(d, 1H)

EXAMPLE 99 Synthesis of1-(1-Methyl-1H-imidazol-5-yl)methyl-3-(morpholin-4-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(99)

To the compound prepared in Example 85 was introduced trityl protectinggroup according to the same procedure as Preparation 28-1), and then thetitle compound was obtained in a yield of 55% by applying the proceduresdescribed in Preparation 29-2) and 29-3) using methyliodide.

¹H NMR(CDCl₃) δ 2.80-3.45(m, 8H), 3.58(s, 3H), 5.19(s, 2H), 6.75(d, 1H),7.18(d, 1H), 7.21(s, 1H), 7.35(d, 1H), 7.40-7.50(m, 3H), 7.72(d, 1H),8.03(d, 1H)

FAB MS: 401 (M+1)

EXAMPLE 100 Synthesis of(S)-1-[1-(4-cyanobenzyl)-1H-imidazol-5-yl]methyl-3-[N-(1-methoxycarbonyl-3-methylthio)propyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole(100)

100-1)1-[1-(4-Cyanobenzyl)-1H-imidazol-5-ylmethyl]-3-hydroxycarbonyl-4-(naphthalen-1-yl)-1H-pyrrole

The title compound was obtained in a yield of 75% from the compoundsprepared in Example 80-2) and Preparation 29-5) by sequentially applyingthe procedures of Example 73 and Example 80-4).

¹H NMR(CDCl₃+CD₃OD) δ 5.02(s, 2H), 5.10(s, 2H), 6.76(s, 1H), 7.07(m,2H), 7.25-7.82(m, 12H)

100-2)(S)-1-[1-(4-Cyanobenzyl)-1H-imidazol-5-yl]methyl-3-[N-(1-methoxycarbonyl-3-methylthio)propyl]carbamoyl)-4-(naphthalen-1-yl)-1H-pyrrole

The title compound was obtained in a yield of 35% according to the sameprocedure as Example 80-5) except that the compound prepared in Example100-1) was used.

¹H NMR(CDCl₃) δ 1.85(s, 3H), 2.04(m, 1H), 2.13(m, 1H), 2.42(t, 2H),3.61(s, 3H), 4.83(m, 1H), 5.02(s, 2H), 5.11(s, 2H), 6.63(s, 1H), 7.01(d,2H), 7.13(d, 1H), 7.22-7.43(m, 7H), 7.65-7.92(m, 4H)

FAB MS: 578 (M+1)

EXAMPLE 101 Synthesis of(S)-1-[1-(4-cyanobenzyl)-1H-imidazol-5-yl]methyl-3-[N-(1-hydroxycarbonyl-3-methylthio)propyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole(101)

Lithium salt of the title compound was obtained in a yield of 96%according to the similar procedure as Example 81 from the compoundprepared in Example 100-2).

¹H NMR(CDCl₃+CD₃OD) δ 1.82(s, 3H), 2.00(m, 1H), 2.11(m, 1H), 2.36(t,2H), 4.82(m, 1H), 4.89(s, 2H), 5.02(s, 2H), 6.49(s, 1H), 6.88(d, 2H),7.11(d, 1H), 7.17-7.32(m, 7H), 7.62-7.83(m, 4H)

FAB MS 564 (M+1)

EXAMPLES 102 AND 103

The compounds represented in the following Table 5 were obtainedaccording to the similar procedure as Examples 100 and 101.

TABLE 5 FAB COM. MS NO. ¹H NMR δ M + 1 102 (CDCl₃) 0.67(d, 3H), 0.78(d,3H), 0.82(m, 1H), 560 0.90(m, 1H), 1.10(m, 1H), 3.52(s, 3H), 4.32(m,1H), 5.02(s, 2H), 5.17(s, 2H), 6.72(s, 1H), 6.83(s, 1H), 7.23-7.34(m,3H), 7.41-7.92(m, 10H) 103 (CDCl₃ + CD₃OD) 0.62(d, 3H), 0.71(d, 3H),0.79(m, 546 1H), 0.88(m, 1H), 0.98(m, 1H), 4.12(m, 1H), 4.97(s, 2H),5.08(s, 2H), 6.77(s, 1H), 6.82(s, 1H), 7.14- 7.30(m, 4H), 7.38-7.84(m,9H)

EXAMPLES 104 AND 105

The compounds represented in the following Table 6 were obtainedaccording to the similar procedure as Example 101.

TABLE 6 FAB COM. MS NO. ¹H NMR (CDCl₃) δ (M + 1) 104 1.95(brs, 2H),2.33(brs, 1H), 2.95(brs, 5H), 4.93(s, 502 2H), 5.05(s, 2H), 6.62(s, 1H),7.05(s, 1H), 7.11(d, 2H), 7.28(m, 2H), 7.51(m, 3H), 7.63(m, 3H), 7.81-7.88(m, 2H), 7.95(d, 1H) 105 1.12(brs, 2H), 1.88(brs, 2H), 1.90(s, 3H),2.95(brs, 515 2H), 3.34(brs, 2H), 4.97(s, 2H), 5.07(s, 2H), 6.60(s, 1H),7.02(s, 1H), 7.10(d, 2H), 7.29(m, 2H), 7.46(m, 3H), 7.60(m, 3H), 7.80(d,1H), 7.85(d, 1H), 7.97(d, 1H)

EXAMPLE 106 Synthesis of1-[2-(1H-imidazol-1-yl)ethyl]-3-(morpholin-4-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(106)

106-1) 2-(1H-Imidazol-1-yl)ethyl p-tosylate

0.24 g(2.41 mmol) of 2-(1H-imidazol-1-yl)ethanol and 0.55 g(2.88 mmol)of tosylchloride were dissolved in 20 ml of dichloromethane, 0.67 ml oftriethylamine was slowly added thereto at 0° C., and the mixture wasstirred at room temperature for 4 hours. The organic solvent was removedunder reduced pressure. The residue was dissolved in 10 ml of ethylacetate, washed sequentially with 1N hydrochloric acid solution,saturated sodium bicarbonate solution and aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate and then concentrated.The residue was subjected to column chromatography(eluent:dichloromethane/methanol=20/1, v/v) to give 0.30 g(1.13 mmol, Yield 47%)of the title compound.

¹H NMR(CDCl₃) δ 2.42(s, 3H), 4.17-4.28(m, 4H), 6.88(s, 1H), 6.99(s, 1H),7.29(d, 2H), 7.45(s, 1H), 7.64(d, 2H)

106-2) 3-Hydroxycarbonyl-4-(naphthalen-1-yl)-1H-pyrrole

The title compound was obtained in a yield of 80% by hydrolyzing thecompound prepared in Example 80-2) according to the same procedure asExample 80-4). ¹H NMR (CDCl₃+CD₃OD) δ 7.12(m, 3H), 7.20-7.31(m, 3H),7.50(d, 1H), 7.68(d, 1H), 7.76(d, 1H)

106-3) 3-(Morpholin-4-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole

The title compound was obtained in a yield of 99% according to the sameprocedure as Example 80-5) from the compound prepared in Example 106-2)and morpholine.

¹H NMR (CDCl₃) δ 2.68-3.62(brs, 8H), 6.88(s, 1H), 7.20(s. 1H),7.30-7.62(m, 4H), 7.78(d, 1H), 7.85(d, 1H), 8.08(d, 1H), 10.34(s, 1H)

106-4)1-[2-(1H-Imidazol-1-yl)ethyl]-3-(morpholin-4-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole

The title compound was obtained in a yield of 51% by reacting thecompound prepared in Example 106-1) with the compound prepared inExample 106-3) according to the same procedure as Example 44-3).

¹H NMR (CDCl₃) δ 2.20-3.72(brs, 12H), 7.20(s, 1H), 7.40-7.55(m, 8H),7.82(d, 1H), 7.88(d, 1H), 8.05(d, 1H)

FAB MS: 401 (M+1)

EXAMPLE 107 Synthesis of(S)-1-[3-(1H-imidazol-4-yl)propyl]-3-[N-(1-methoxycarbonyl-3-methylthio)propyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole(107)

107-1)3-Ethoxycarbonyl-4-(naphthalen-1-yl)-1-[3-(1-trityl-1H-imidazol-4-yl)allyl]-1H-pyrrole

The title compound was obtained in a yield of 85% by reacting thecompound prepared in Example 80-2) with the compound prepared inPreparation 30-4) according to the same procedure as Example 44-3).

¹H NMR (CDCl₃) δ 0.82(t, 3H), 3.95(q, 2H), 4.67(s, 2H), 6.23(d, 1H),6.47(m, 1H), 6.63(s, 1H), 7.02(s, 1H), 7.25-7.81(m, 24H)

107-2)3-Ethoxycarbonyl-4-(naphthalen-1-yl)-1-[3-(1-trityl-1H-imidazol-4-yl)propyl]-1H-pyrrole

300 mg(0.49 mmol) of the compound prepared in Example 107-1) wasdissolved in 2 ml of methanol, catalytic amount of Pd/C was addedthereto, and the mixture was stirred for 1 hour under hydrogenatmosphere. The mixture was filtered to remove the catalyst and thesolvent therein was removed under reduced pressure. The residue wassubject to column chromatography(eluent: dichloromethane/methanol=98/2,v/v) to give 246 mg(0.40 mmol, Yield 82%) of the title compound.

¹H NMR (CDCl₃) δ 0.92(t, 3H), 2.22(m, 2H), 2.73(t, 2H), 4.01(m, 4H),6.70(s, 1H), 6.82(s, 1H), 7.32-7.73(m, 21H), 7.91(m, 3H)

107-3)(S)-1-[3-(1H-Imidazol-4-yl)propyl]-3-[N-(1-methoxycarbonyl-3-methylthio)propyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole

The compound prepared in Example 107-2) was treated according to theprocedures of Example 44-4) and 80-4) to eliminate the trityl group andhydrolyze. Then, the product thus obtained was reacted with(L)-methionine methylester according to the same procedure as Example80-5) to give the title compound in a yield of 29%.

¹H NMR (CDCl₃) δ 1.65(m, 2H), 1.90(s, 3H), 2.12(m, 2H), 2.31(m, 2H),2.73(m, 2H), 3.54(s, 3H), 4.02(m, 2H), 4.56(m, 1H), 5.77(d, 1H), 6.72(s,1H), 6.90(s, 1H), 7.42-7.67(m, 7H), 7.82-8.01(m, 5H)

FAB MS: 491 (M+1)

EXAMPLE 108 Synthesis of(S)-3-[N-(1-hydroxycarbonyl-3-methylthio)propyl]carbamoyl-1-[3-(1H-imidazol-4-yl)propyl]-4naphthalen-1-yl)-1H-pyrrole(108)

The title compound was obtained in a yield of 95% according to the sameprocedure as Example 81 except that the compound prepared in Example107-3) was used.

¹H NMR (CDCl₃) δ 1.57(m, 2H), 1.88(s, 3H), 2.08(m, 2H), 2.29(m, 2H),2.77(m, 2H), 4.12(m, 2H), 4.49(m, 1H), 5.69(d, 1H), 6.77(s, 1H), 6.92(s,1H), 7.34-7.58(m, 7H), 7.80-7.89(m, 5H)

FAB MS: 477 (M+1)

EXAMPLE 109 Synthesis of1-[3-(1H-imidazol-4-yl)propyl]-3-(morpholin-4-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(109)

The title compound was obtained in a yield of 42% according to the sameprocedure as Example 107-3) except that morpholine was used to thecompound prepared in Example 107-2).

¹H NMR (CDCl₃) δ 2.16(m, 2H), 2.35(brs, 2H), 2.63(m, 2H), 2.80-3.50(brs,6H), 3.54(s, 3H), 3.96(m, 2H), 6.74(d, 1H), 6.76(s, 1H), 7.07(s, 1H),7.33(t, 1H), 7.36-7.50(m, 4H), 7.76(d, 1H), 7.84(d, 1H), 8.08(d, 1H)

FAB MS 415 (M+1)

EXAMPLE 110 Synthesis of1-[1-(4-Cyanobenzyl)-1H-imidazol-5-yl]methyl-3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole(110)

110-1)3-[N-(2-Methoxyethyl)-N-methyl]carbamoyl)-4-(naphthalen-1-yl)-1H-pyrrole

100 mg(0.42 mmol) of the compound prepared in Example 106-2) and 38mg(0.4 mmol) of N-(2-methoxyethyl)-N-methylamine were reacted accordingto the similar procedure as Example 80-5) to give 110 mg(0.35 mmol,Yield 85%) of the title compound.

¹H NMR (CDCl₃) δ 2.21(s, 3H), 2.64(brs, 1H), 2.75(brs, 1H), 3.02(s, 3H),3.13(brs, 1H), 3.32(brs, 1H), 6.72(s, 1H), 7.05(m, 2H), 7.21(m, 2H),7.54(m, 1H), 7.78(m, 2H), 8.04(d, 1H), 8.78(brs, 1H)

110-2)1-[1-(4-Cyanobenzyl)-1H-imidazol-5-yl]methyl-3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole

98 mg(0.32 mmol) of the compound prepared in Example 110-1) and 85mg(0.32 mmol) of the compound prepared in Preparation 29-5) were reactedaccording to the similar procedure as Example 44-3) to give 115 mg(0.23mmol, Yield 72%) of the title compound.

¹H NMR (CDCl₃) δ 2.41(s, 3H), 2.75(brs, 2H), 3.07(s, 3H), 3.17(brs, 1H),3.32(brs, 1H), 4.91(s, 2H), 5.11(s, 2H), 6.71(s, 1H), 7.05(s, 1H),7.17(d, 1H), 7.40-7.68(m, 9H), 7.78(d, 1H), 7.88(d, 1H), 8.06(d, 1H)

FAB MS 504 (M+1)

EXAMPLE 111 Synthesis of1-[1-(4-Bromobenzyl)-1H-imidazol-5-yl]methyl-3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole(111)

105 mg(0.29 mmol) of the compound prepared in Example 110-1) and 78mg(0.29 mmol) of the compound prepared in Preparation 32-2) were reactedaccording to the similar procedure as Example 44-3) to give 121 mg(0.21mmol, Yield 75%) of the title compound.

¹H NMR (CDCl₃) δ 2.37(s, 3H), 2.72(brs, 2H), 3.04(s, 3H), 3.15(brs, 1H),3.31(brs, 1H), 4.95(s, 21), 5.10(s, 2H), 6.67(s, 1H), 7.11(s, 1H),7.23-7.65(m, 10H), 7.81(d, 1H), 7.89(d, 1H), 8.02(d, 1H)

FAB MS 557 (M+1)

EXAMPLE 112 Synthesis of1-[1-(4-Bromobenzyl)-1H-imidazol-5-yl]methyl-3-(morpholin-4-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(112)

100 mg(0.33 mmol) of the compound prepared in Example 106-3) and 105mg(0.33 mmol) of the compound prepared in Preparation 32-2) were reactedaccording to the similar procedure as Example 44-3) to give 130 mg(0.23mmol, Yield 71%) of the title compound.

¹H NMR (CDCl₃) δ 2.04(brs, 2H), 2.25(brs, 1H), 3.03(brs, 5H), 4.93(s,2H), 5.07(s, 2H), 6.62(s, 1H), 7.10(m, 3H), 7.29(m, 2H), 7.41(m, 3H),7.60(m, 3H), 7.81(d, 1H), 7.89(d, 1H), 8.01(d, 1H)

FAB MS 555 (M+1)

EXAMPLE 113 Synthesis of1-[1-(4-Cyanobenzyl)-1H-imidazol-5-yl]methyl-3-(morpholin-4-yl)thiocarbonyl-4-(naphthalen-1-yl)-1H-pyrrole(113)

20 mg(0.04 mmol) of the compound prepared in Example 104 and 18 mg of2,4-bis(phenylthio)-1,3-dithia-2,4-diphosphatan-2,4-disulfide weredissolved in 1 ml of tetrahydrofuran, and the mixture was stirred atroom temperature for 3 hours. To the reaction solution was added 2 ml ofsaturated sodium bicarbonate solution. The resulting mixture wasextracted with ethyl acetate and dried over anhydrous sodium sulfate.The organic solvent was removed under reduced pressure and the residuewas subjected to column chromatography(eluent:dichloromethane/methanol=9/1, v/v) to give 9 mg(0.017 mmol, Yield 43%)of the title compound.

¹H NMR (CDCl₃) δ 1.88(brs, 2H), 2.64(brs, 6H), 4.86(s, 2H), 5.01(s, 2H),6.67(s, 1H), 7.14(m, 3H), 7.26-7.58(m, 8H), 7.81(m. 2H), 8.03(d, 1H)

FAB MS: 518 (M+1)

EXAMPLE 114 Synthesis of3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-1-(1-methyl-1H-imidazol-5-yl)methyl-4-(naphthalen-1-yl)-1H-pyrrole(114)

114-1) 4-(Naphthalen-1-yl)-1H-pyrrole-3-carboxylic acid

2.64 g(10 mmol) of the compound prepared in Example 80-2) was dissolvedin 50 ml of 50% ethanol, and 2.24 g(40 mmol) of potassium hydroxide wasadded thereto. The reaction mixture was refluxed for 7 hours, cooleddown to room temperature, adjusted to pH 4-5, extracted with ethylacetate, dried over anhydrous sodium sulfate. The solvent was removedunder reduced pressure to obtain 1.62 g(8.1 mmol, Yield 81%) of thetitle compound. The product thus obtained was directly used in the nextreaction without purification.

¹H NMR(CDCl₃) δ 6.60(s, 1H), 7.32-7.49(m, 5H), 7.54(s, 1H), 7.84(m, 2H),9.92(s, 1H)

FAB (M+H): 236

114-2)3-[N-(2-Methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole

234 mg(1 mmol) of the compound prepared in Example 114-1) was dissolvedin 2 ml of dimethylformamide, and then 230 mg(1.2 mmol) of EDC, 101 mg(1mmol) of triethylamine and 162 mg(1.2 mmol) of HOBT were added thereto.The resulting mixture was stirred at 0° C. for 5 minutes. To thereaction solution was added 124 mg(1 mmol) ofN-(2-methoxyethyl)-N-methylamine hydrochloride, which was then stirredat room temperature for 5 hours. The solvent was removed under reducedpressure and then 10 ml of saturated potassium carbonate solution wasadded to the residue. The resulting solution was extracted with 20 ml ofethyl acetate, washed with 10 ml of 1N aqueous hydrochloric acidsolution, washed with aqueous sodium chloride solution and water, driedover anhydrous sodium sulfate and concentrated to give 246 mg(0.8 mmol)of the title compound.

¹H NMR(CDCl₃) δ 2.46(s, 2H), 2.80-3.40(m, 7H), 3.40(s, 1H), 6.80(s, 1H),7.00(s, 1H), 7.42(m, 4H), 7.73(d, 1H), 7.81(d, 1H), 8.17(d, 1H), 10.66(s, 1H)

FAB (M+H): 309

114-3)1-(1-Methyl-1H-imidazol-5-yl)methyl-3-[N-(2-methoxyethyl)-N-methyl]carbamoyl)-4-(naphthalen-1-yl)-1H-pyrrole

618 mg(2.0 mmol) of the compound prepared in Example 114-2) wasdissolved in 10 ml of dimethylformamide, 264 mg(6.6 mmol) of sodiumhydride(60%) was added thereto at 0° C. and then the mixture was stirredfor 5 minutes. To the mixture was added 367 mg(2.2 mmol) of5-chloromethyl-1-methylimidazole hydrochloride and the whole mixture wasstirred at room temperature for 5 hours. The solvent was removed bydistillation under reduced pressure and 10 ml of water was added to theresidue. The mixture was then extracted twice with 20 ml of ethylacetate, dried over anhydrous sodium sulfate, concentrated, andsubjected to silica gel column chromatography(eluent:dichloromethane/methanol=90/10, v/v) to obtain 644 mg(Yield 80%) of thetitle compound.

¹H NMR(CDCl₃) δ 2.42(s, 2H), 2.71(m, 1H), 3.10(brs, 6H), 3.30)(brs, 1H),3.50(s, 3H), 5.09(s, 2H), 6.70(s, 1H), 7.05(s, 1H), 7.15(s, 1H),7.30-7.49 (m, 4H), 7.72(d, 1H), 7.84(d, 2H), 8.08(d, 1H)

FAB (M+H): 403

EXAMPLE 115 Synthesis of1-(1-Isobutyl-1H-imidazol-5-yl)methyl-3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole

618 mg(2.0 mmol) of the compound prepared in Example 114-2) wasdissolved in 10 ml of dimethylformamide, 264 mg(6.6 mmol) of sodiumhydride(60%) was added thereto at 0° C., and the mixture was stirred for5 minutes. 459 mg(2.2 mmol) of the compound prepared in Preparation33-2) was added to the mixture, which was then stirred at roomtemperature for 5 hours. The solvent was removed by distillation underreduced pressure and loge of water was added to the residue. Theresulting mixture was extracted twice with 20 ml of ethyl acetate, driedover anhydrous sodium sulfate, concentrated and subjected to silica gelcolumn chromatography(eluent: dichloromethane/methanol=90/10, v/v) toobtain 667 mg(Yield 75%) of the title compound.

¹H NMR(CDCl₃) δ 0.90(d, 6H), 1.75(m, 1H), 2.41(brs, 2H), 2.72(brs, 1H),3.01(brs, 6H), 3.32(brs, 1H), 3.62(d, 2H), 5.13(s, 2H), 6.72(s, 1H),7.09(s, 1H), 7.19(s, 1H), 7.30-7.49(m, 4H), 7.78(d, 1H), 7.84(d, 2H),8.08 d, 1H)

FAB (M+H): 445

EXAMPLE 116 Synthesis of1-(1-Cyclohexylmethyl-1H-imidazol-5-yl)methyl-3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole(116)

618 mg(2.0 mmol) of the compound prepared in Example 114-2) wasdissolved in 10 ml of dimethylformamide, 264 mg(6.6 mmol) of sodiumhydride(60%) was added thereto at 0° C., and the mixture was stirred for5 minutes. 647 mg(2.2 mmol) of the compound prepared in Preparation34-2) was added to the mixture, which was then stirred at roomtemperature for 5 hours. The solvent was removed by distillation underreduced pressure and 10 ml of water was added to the residue. Theresulting mixture was extracted twice with 20 ml of ethyl acetate, driedover anhydrous sodium sulfate, concentrated and subjected to silica gelcolumn chromatography(eluent: dichloromethane/methanol=90/10, v/v) toobtain 726 g(Yield 75%) of the title compound.

¹H NMR(CDCl₃) δ 0.87(m, 2H), 1.12(m, 3H), 1.30(brs, 1H), 1.40-1.80(m,5H), 2.41(brs, 2H), 2.72(brs, 1H), 3.01(brs, 6H), 3.32(brs, 1H), 3.63(d,2H), 5.09(s, 2H), 6.72(s, 1H), 7.09(s, 1H), 7.19(s, 1H), 7.25(s, 1H),7.30-7.49 (m, 3H), 7.78(d, 1H), 7.83(d, 2H), 8.08(d, 1H)

FAB (M+H): 485

EXAMPLE 117 Synthesis of3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1-(1-pentyl-1H-imidazol-5-yl)methyl-1H-pyrrole(117)

618 mg(2.0 mmol) of the compound prepared in Example 114-2) wasdissolved in 10 ml of dimethylformamide, 264 mg(6.6 mmol) of sodiumhydride(60%) was added thereto at 0° C., and the mixture was stirred for5 minutes. 429 mg(2.2 mmol) of the compound prepared in Preparation35-2) was added to the mixture, which was then stirred at roomtemperature for 5 hours. The solvent was removed by distillation underreduced pressure and 10 ml of water was added to the residue. Theresulting mixture was extracted twice with 20 ml of ethyl acetate, driedover anhydrous sodium sulfate, concentrated and subjected to silica gelcolumn chromatography(eluent: dichloromethane/methanol=90/10, v/v) toobtain 714 mg(Yield 78%) of the title compound.

¹H NMR(CDCl₃) δ 0.90(t, 3H), 1.08(brs, 2H), 1.30(m, 2H), 1.45(m, 2H),2.41(brs, 2H), 2.72(brs, 1H), 3.01(brs, 6H), 3.32(brs, 1H), 3.63(t, 2H),5.09 (s, 2H), 6.72(s, 1H), 7.09(s, 1H), 7.19(s, 1H), 7.25(s. 1H),7.30-7.49(m, 3H), 7.78(d, 1H), 7.83(d, 2H), 8.08(d, 1H)

FAB (M+H): 459

EXAMPLE 118 Synthesis of3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1-(1-octyl-1H-imidazol-5-yl)methyl-1H-pyrrole(118)

618 mg(2.0 mmol) of the compound prepared in Example 114-2) wasdissolved in 10 ml of dimethylformamide, 264 mg(6.6 mmol) of sodiumhydride(60%) was added thereto at 0° C., and the mixture was stirred for5 minutes. 508 mg(2.2 mmol) of the compound prepared in Preparation36-2) was added to the mixture, which was then stirred at roomtemperature for 5 hours. The solvent was removed by distillation underreduced pressure and 10 ml of water was added to the residue. Theresulting mixture was extracted twice with 20 ml of ethyl acetate, driedover anhydrous sodium sulfate, concentrated and subjected to silica gelcolumn chromatography(eluent: dichloromethane/methanol=90/10, v/v) toobtain 760 mg(Yield 76%) of the title compound.

¹H NMR(CDCl₃) δ 0.87(t, 3H), 1.17(brs, 2H), 1.30(brs, 10H), 1.44(m, 2H),2.41(brs, 2H), 2.72(brs, 1H), 3.01brs, 6H), 3.32(brs, 1H), 3.62(t, 2H),5.09(s, 2H), 6.72(s, 1H), 7.09(s, 1H), 7.19(s, 1H), 7.25(s, 1H),7.30-7.49 (m, 3H), 7.78(d, 1H), 7.83(d, 2H), 8.08(d, 1H)

FAB (M+H): 501

EXAMPLE 119 Synthesis of1-(1-Decyl-1H-imidazol-5-yl)methyl-3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole(119)

618 mg(2.0 mmol) of the compound prepared in Example 114-2) wasdissolved in 10 ml of dimethylformamide, 264 mg(6.6 mmol) of sodiumhydride(60%) was added thereto at 0° C., and the mixture was stirred for5 minutes. 567 mg(2.2 mmol) of the compound prepared in Preparation37-2) was added to the mixture, which was then stirred at roomtemperature for 5 hours. The solvent was removed by distillation underreduced pressure and 10 ml of water was added to the residue. Theresulting mixture was extracted twice with 20 ml of ethyl acetate, driedover anhydrous sodium sulfate, concentrated and subjected to silica gelcolumn chromatography(eluent: dichloromethane/methanol=90/10, v/v) toobtain 667 mg(Yield 75%) of the title compound.

¹H NMR(CDCl₃) δ 30.87(t, 3H), 1.17(brs, 2H), 1.30(brs, 14H), 1.44(m,2H), 2.41(brs, 2H), 2.72(brs, 1H), 3.01(brs, 6H), 3.32(brs, 1H), 3.62(t,2H), 5.09(s, 2H), 6.72(s, 1H), 7.09(s, 1H), 7.19(s, 1H), 7.25(s, 1H),7.30-7.49 (m, 3H), 7.78(d, 1H), 7.83(d, 2H), 8.08(d, 1H)

FAB (M+H): 529

EXAMPLE 120 Synthesis of3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-1-[1-(3-methylbutyl)-1H-imidazol-5-yl]methyl-4-(naphthalen-1-yl)-1H-pyrrole(120)

618 mg(2.0 mmol) of the compound prepared in Example 114-2) wasdissolved in 10 ml of dimethylformamide, 264 mg(6.6 mmol) of sodiumhydride(60%) was added thereto at 0° C., and the mixture was stirred for5 minutes. 429 mg(2.2 mmol) of the compound prepared in Preparation38-2) was added to the mixture, which was then stirred at roomtemperature for 5 hours. The solvent was removed by distillation underreduced pressure and 10 ml of water was added to the residue. Theresulting mixture was extracted twice with 20 ml of ethyl acetate, driedover anhydrous sodium sulfate, concentrated and subjected to silica gelcolumn chromatography(eluent: dichloromethane/methanol=90/10, v/v) toobtain 667 mg(Yield 75%) of the title compound.

¹H NMR(CDCl₃) δ 0.91(d, 6H), 1.31(q, 2H), 1.67(m, 1H), 2.41(brs, 2H),2.72(brs, 1H), 3.01(brs, 6H), 3.32(brs, 1H), 3.62(t, 2H), 5.09(s, 2H),6.72 (s, 1H), 7.09(s, 1H), 7.19(s, 1H), 7.25(s, 1H), 7.30-7.49(m, 3H),7.78(d, 1H), 7.83(d, 2H), 8.08(d, 1H)

FAB (M+H): 459

EXAMPLE 121 Synthesis of1-[1-(2-Methoxyethyl)-1H-imidazol-5-yl]methyl-3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole(121)

618 mg(2.0 mmol) of the compound prepared in Example 114-2) wasdissolved in 10 ml of dimethylformamide, 264 mg(6.6 mmol) of sodiumhydride(60%) was added thereto at 0° C., and the mixture was stirred for5 minutes. 429 mg(2.2 mmol) of the compound prepared in Preparation39-2) was added to the mixture, which was then stirred at roomtemperature for 5 hours. The solvent was removed by distillation underreduced pressure and 10 ml of water was added to the residue. Theresulting mixture was extracted twice with 20 ml of ethyl acetate, driedover anhydrous sodium sulfate, concentrated and subjected to silica gelcolumn chromatography(eluent: dichloromethane/methanol=90/10, v/v) toobtain 667 mg(Yield 75%) of the title compound.

¹H NMR(CDCl₃) δ 2.41(brs, 2H), 2.72(brs, 1H), 3.01(brs, 6H), 3.32(brs,1H), 3.37(s, 3H), 3.45(t, 2H), 3.63(t, 2H), 5.09(s, 2H), 6.72(s, 1H),7.09 (s, 1H), 7.19(s, 1H), 7.25(s, 1H), 7.30-7.49(m, 3H), 7.78(d, 1H),7.83(d, 2H), 8.08(d, 1H)

FAB (M+H): 447

EXAMPLE 122 Synthesis of3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-1-[1-(3-methoxypropyl)-1H-imidazol-5-yl]methyl-4-(naphthalen-1-yl)-1H-pyrrole(122)

618 mg(2.0 mmol) of the compound prepared in Example 114-2) wasdissolved in 10 ml of dimethylformamide, 264 mg(6.6 mmol) of sodiumhydride(60%) was added thereto at 0° C., and the mixture was stirred for5 minutes. 459 mg(2.2 mmol) of the compound prepared in Preparation40-2) was added to the mixture, which was then stirred at roomtemperature for 5 hours. The solvent was removed by distillation underreduced pressure and 10 ml of water was added to the residue. Theresulting mixture was extracted twice with 20 ml of ethyl acetate, driedover anhydrous sodium sulfate, concentrated and subjected to silica gelcolumn chromatography(eluent: dichloromethane/methanol=90/10, v/v) toobtain 683 Mg(Yield 70%) of the title compound.

¹H NMR(CDCl₃) δ 1.71(m, 2H), 2.41(brs, 2H), 2.72(brs, 1H), 3.01(brs,6H), 3.31(s, 3H), 3.32(brs, 1H), 3.48(t, 2H), 3.63(t, 2H), 5.09(s, 2H),6.72 (s, 1H), 7.09(s, 1H), 7.19(s, 1H), 7.25(s, 1H), 7.30-7.49(m, 3H),7.78(d, 1H), 7.83(d, 2H), 8.08(d, 1H)

FAB (M+H): 461

EXAMPLE 123 Synthesis of1-[1-(3-Ethoxypropyl)-1H-imidazol-5-yl]methyl-3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole(123)

618 mg(2.0 mmol) of the compound prepared in Example 114-2) wasdissolved in 10 ml of dimethylformamide, 264 mg(6.6 mmol) of sodiumhydride(60%) was added thereto at 0° C., and the mixture was stirred for5 minutes. 459 mg(2.2 mmol) of the compound prepared in Preparation41-2) was added to the mixture, which was then stirred at roomtemperature for 5 hours. The solvent was removed by distillation underreduced pressure and 10 ml of water was added to the residue. Theresulting mixture was extracted twice with 20 ml of ethyl acetate, driedover anhydrous sodium sulfate, concentrated and subjected to silica gelcolumn chromatography(eluent: dichloromethane/methanol=90/10, v/v) toobtain 712 mg(Yield 71%) of the title compound.

¹H NMR(CDCl₃) δ 1.20(t, 3H), 1.70(m, 2H), 2.4 l(brs. 2H), 2.72(brs, 1H),3.01(brs, 6H), 3.32(brs, 1H), 3.50(m, 4H). 3.63(t, 2H), 5.09(s, 2H),6.72(s, 1H), 7.09(s, 1H), 7.19(s, 1H), 7.25(s, 1H), 7.30-7.49(m, 3H),7.78(d, 1H), 7.83(d, 2H), 8.08(d, 1H)

FAB (M+H): 475

EXAMPLE 124 Synthesis of1-[1-(3-Isopropoxypropyl)-1H-imidazol-5-yl]methyl-3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole(124)

618 mg(2.0 mmol) of the compound prepared in Example 114-2) wasdissolved in 10 ml of dimethylformamide, 264 mg(6.6 mmol) of sodiumhydride(60%) was added thereto at 0° C., and the mixture was stirred for5 minutes. 459 mg(2.2 mmol) of the compound prepared in Preparation42-2) was added to the mixture, which was then stirred at roomtemperature for 5 hours. The solvent was removed by distillation underreduced pressure and 10 ml of water was added to the residue. Theresulting mixture was extracted twice with 20 ml of ethyl acetate, driedover anhydrous sodium sulfate, concentrated and subjected to silica gelcolumn chromatography(eluent: dichloromethane/methanol=90/10, v/v) toobtain 751 mg(Yield 73%) of the title compound.

¹H NMR(CDCl₃) δ 1.16(d, 6H), 1.70(m, 2H), 2.41(brs, 2H), 2.72(brs, 1H),3.01(brs, 6H), 3.32(brs, 1H), 3.45-3.55(m, 3H), 3.63(t, 2H), 5.09(s,2H), 6.72(s, 1H), 7.09(s, 1H), 7.19(s, 1H), 7.25(s, 1H), 7.30-7.49(m,3H), 7.78 (d, 1H), 7.83(d, 2H), 8.08(d, 1H)

FAB (M+H): 489

EXAMPLE 125 Synthesis of1-[1-(4-Bromobenzyl)-1H-imidazol-5-yl]methyl-3-[4-methylpiperazin-1-yl]carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(125)

125-1) 3-[4-Methylpiperazin-1-yl]carbonyl-4-(naphthalen-1-yl)-1H-pyrrole

The title compound was obtained in a yield of 90% according to the sameprocedure as Example 80-5) from the compound prepared in Example 106-2)and 4-methylpiperazine.

¹H NMR (CDCl₃) δ 1.15(br, 2H), 1.87(br, 2H), 1.92(s, 3H), 2.96(br, 2H),3.41(br, 2H), 6.83(s, 1I1), 7.09(s, 1H), 7.36-7.42(m, 4H), 7.73(d, 1H),7.75 (d, 1H), 8.10(d; 1H), 10.52(s, 1H)

FAB (M+H): 320

125-2)1-[1-(4-Bromobenzyl)-1H-imidazol-5-yl]methyl-3-[4-methylpiperazin-1-yl]carbonyl-4-(naphthalen-1-yl)-1H-pyrrole

64 mg(0.2 mmol) of the compound prepared in Example 125-1) was dissolvedin 2 ml of dimethylformamide, 26 mg(0.66 mmol) of sodium hydride wasadded thereto at 0° C., and the mixture was stirred for 5 minutes. 66mg(0.22 mmol) of the compound prepared in Preparation 32-2) was added tothe mixture, which was then stirred at room temperature for 5 hours. Thesolvent was removed by distillation under reduced pressure and 10 ml ofwater was added to the residue. The resulting mixture was extractedtwice with 10 ml of ethyl acetate, dried over anhydrous sodium sulfate,concentrated and subjected to silica gel column chromatography(eluent:dichloromethane/methanol=90/10, v/v) to obtain 91 mg(Yield 80%) of thetitle compound.

¹H NMR (CDCl₃) δ 1.15(br, 2H), 1.77(br, 2H), 1.86(s, 3H), 2.82(br, 2H),3.28(br, 2H), 4.87(s, 2H), 3.88(s, 2H), 6.55(s, 1H), 6.79(d, 2H),6.97(s, 1H), 7.16(s, 1H), 7.36(d, 1H), 7.36-7.39(m, 5H), 7.50(s, 1H),7.71(d, 1H), 7.79(d, 1H), 7.93(d, 1H)

FAB (M+H): 568

EXAMPLE 126 Synthesis of1-[1-(4-Chlorobenzyl)-1H-imidazol-5-yl]methyl-3-[4-methylpiperazin-1-yl]carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(126)

64 mg(0.2 mmol) of the compound prepared in Example 125-1) was dissolvedin 2 ml of dimethylformamide, 26 mg(0.66 mmol) of sodium hydride wasadded thereto at 0° C., and the mixture was stirred for 5 minutes. 55mg(0.22 mmol) of 1-(4-chlorobenzyl)-5-chloromethylimidazolehydrochloride prepared according to the similar procedure as Preparation32 was added to the mixture, which was then stirred at room temperaturefor 5 hours. The solvent was removed by distillation under reducedpressure and 10 ml of water was added to the residue. The resultingmixture was extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated and subjected to silica gelcolumn chromatography(eluent: dichloromethane/methanol=90/10, v/v) toobtain 77 mg(Yield 57%) of the title compound.

¹H NMR (CDCl₃) δ 1.15(br, 2H), 1.77(br, 2H), 1.86(s, 3H), 2.82(br, 2H),3.28(br, 2H), 4.92(s, 2H), 4.95(s, 2H), 6.60(s, 1H), 6.91(d, 2H),6.01(s, 1H), 7.22(s, 1H), 7.26-7.36(m, 3H), 7.36-7.48(m, 2H), 7.56(s,1H), 7.77(d, 1H), 7.82(d, 1H), 7.93(d, 1H)

FAB (M+H): 524

EXAMPLE 127 Synthesis of1-[1-(4-Fluorobenzyl)-1H-imidazol-5-yl]methyl-3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole(127)

62 g(0.2 mmol) of the compound prepared in Example 114-2) was dissolvedin 2 ml of dimethylformamide, 26 mg(0.66 mmol) of sodium hydride wasadded thereto at 0° C., and the mixture was stirred for 5 minutes. 51mg(0.22 mmol) of 1-(4-fluorobenzyl)-5-chloromethylimidazolehydrochloride prepared according to the similar procedure as Preparation32 was added to the mixture, which was then stirred at room temperaturefor 5 hours. The solvent was removed by distillation under reducedpressure and 10 ml of water was added to the residue. The resultingmixture was extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated and subjected to silica gelcolumn chromatography(eluent: dichloromethane/methanol=90/10, v/v) toobtain 77 mg(Yield 80%) of the title compound.

¹H NMR(CDCl₃) δ 2.12(br, 3H), 2.72(br, 1H), 3.00-3.20(m, 5H), 3.32(s,1H), 4.97(s, 2H), 3.98(s, 2H), 6.64(s, 1H), 6.95-7.10(m, 5H), 7.21(s,1H), 7.33(m, 1H), 7.40-7.51(m, 3H), 7.66(s, 1H), 7.74(d, 1H), 7.81(d,1H), 8.08(d, 1H)

FAB (M+H): 497

EXAMPLE 128 Synthesis of1-[1-(4-Fluorobenzyl)-1H-imidazol-5-yl]methyl-3-[4-methylpiperazin-1-yl]carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(128)

64 mg(0.2 mmol) of the compound prepared in Example 125-1) was dissolvedin 2 ml of dimethylformamide, 26 mg(0.66 mmol) of sodium hydride wasadded thereto at 0° C., and the mixture was stirred for 5 minutes. 51mg(0.22 mmol) of 1-(4-fluorobenzyl)-5-chloromethylimidazolehydrochloride prepared according to the similar procedure as Preparation32 was added to the mixture, which was then stirred at room temperaturefor 5 hours. The solvent was removed by distillation under reducedpressure and 10 ml of water was added to the residue. The resultingmixture was extracted twice with 10 ml of ethyl acetate, dried overanhydrous sodium sulfate, concentrated and subjected to silica gelcolumn chromatography(eluent: dichloromethane/methanol=90/10, v/v) toobtain 79 mg(Yield 80%) of the title compound.

¹H NMR (CDCl₃) δ 1.15(br, 2H), 1.77(br, 2H), 1.86(s, 3H), 2.82(br, 2H),3.28(br, 2H), 4.92(s, 2H), 4.97(s, 2H), 6.60(s, 1H), 6.93(d, 2H),6.01(s, 1H), 7.22(s, 1H), 7.25-7.36(m, 3H), 7.36-7.47(m, 2H), 7.57(s,1H), 7.78(d, 1H), 7.82(d, 1H), 7.93(d, 1H)

FAB (M+H) 508

Preparation 43 Synthesis of 5-Chloromethyl-1-(4-methoxybenzyl)imidazoleHydrochloride

43-1) 5-Hydroxymethyl-1-(4-methoxybenzyl)imidazole

The title compound was obtained in a yield of 30% according to the sameprocedure as Preparation 31-1) using dihydroxyacetone and4-methoxybenzylamine hydrochloride as starting materials.

¹H NMR(CDCl₃+CD₃OD) δ 3.75(s, 3H), 4.50(s, 2H), 5.15(s, 2H), 6.86(m,3H), 7.08(d, 2H), 7.42(s, 1H)

FAB (M+H): 219

43-2) 5-Chloromethyl-1-(4-methoxybenzyl)imidazole hydrochloride

The title compound was obtained in a yield of 95% according to the sameprocedure as Preparation 28-2) except that the compound prepared inPreparation 43-1) was used as a starting material.

Preparation 44 Synthesis of 5-Chloromethyl-1-(3-chlorobenzyl)imidazoleHydrochloride

44-1) 5-Hydroxymethyl-1-(3-chlorobenzyl)imidazole

The title compound was obtained in a yield of 60% according to the sameprocedure as Preparation 31-1) using dihydroxyacetone and3-chlorobenzylamine hydrochloride as starting materials.

¹H NMR(CDCl₃+CD₃OD) δ 3.81(s, 3H), 4.47(s, 2H), 5.25(s, 2H), 6.99(s,1H), 7.05(m, 1H), 7.14(s, 1H), 7.30(d, 2H), 7.61(s, 1H)

FAB (M+H): 239.5

44-2) 5-Chloromethyl-1-(3-chlorobenzyl)imidazole hydrochloride

The title compound was obtained in a yield of 92% according to the sameprocedure as Preparation 28-2) except that the compound prepared inPreparation 44-1) was used as starting material.

Preparation 45 Synthesis of 5-Chloromethyl-1-(2-chlorobenzyl)imidazoleHydrochloride

45-1) 5-Hydroxymethyl-1-(2-chlorobenzyl)imidazole

The title compound was obtained in a yield of 60% according to the sameprocedure as Preparation 31-1) using dihydroxyacetone and2-chlorobenzylamine hydrochloride as starting materials.

¹H NMR(CDCl₃) δ 3.24(s, 2H), 4.44(s, 2H), 5.26(s, 2H), 6.78(d, 1H),6.90(s, 1H), 7.15(m, 1H), 7.21(m, 1H), 7.34(d, 1H), 7.38(s, 1H)

FAB (M+H): 239.5

45-2) 5-Chloromethyl-1-(2-chlorobenzyl)imidazole hydrochloride

The title compound was obtained in a yield of 92% according to the sameprocedure as Preparation 28-2) except that the compound prepared inPreparation 45-1) was used as a starting material.

Preparation 46 Synthesis of 5-Chloromethyl-1-(2-fluorobenzyl)imidazoleHydrochloride

46-1) 5-Hydroxymethyl-1-(2-fluorobenzyl)imidazole

The title compound was obtained in a yield of 71% according to the sameprocedure as Preparation 31-1) using dihydroxyacetone and2-fluorobenzylamine hydrochloride as starting materials.

¹H NMR(CDCl₃) δ 3.25(s, 2H), 4.45(s, 2H), 5.27(s, 2H), 6.79(d, 1H),7.17(m, 1H), 7.26(m, 1H), 7.35(d, 1H), 7.38(s, 1H)

FAB (M+H): 223

46-2) 5-Chloromethyl-1-(2-fluorobenzyl)imidazole hydrochloride

The title compound was obtained in a yield of 93% according to the sameprocedure as Preparation 28-2) except that the compound prepared inPreparation 46-1) was used as a starting material.

Preparation 47 Synthesis of 5-Chloromethyl-1-(4-methylbenzyl)imidazoleHydrochloride

47-1) 5-Hydroxymethyl-1-(4-methylbenzyl)imidazole

The title compound was obtained in a yield of 65% according to the sameprocedure as Preparation 31-1) using dihydroxyacetone and4-methylbenzylamine hydrochloride as starting materials.

¹H NMR(CDCl₃) δ 2.32(s, 3H), 4.50(s, 2H), 5.19(s, 2H), 6.95(s, 1H),7.05(d, 2H), 7.15(d, 2H), 7.59(s, 1H)

FAB (M+H): 219

47-2) 5-Chloromethyl-1-(4-methylbenzyl)imidazole hydrochloride

The title compound was obtained in a yield of 91% according to the sameprocedure as Preparation 28-2) except that the compound prepared inPreparation 47-1) was used as a starting material.

Preparation 48 Synthesis of 5-Chloromethyl-1-(3-methylbenzyl)imidazoleHydrochloride

48-1) 5-Hydroxymethyl-1-(3-methylbenzyl)imidazole

The title compound was obtained in a yield of 60% according to the sameprocedure as Preparation 31-1) using dihydroxyacetone and3-methylbenzylamine hydrochloride as starting materials.

¹H NMR(CDCl₃) δ 2.27(s, 3H), 4.45(s, 2H), 4.52(br, 1H), 5.13(s, 2H),6.80(d, 1H), 6.90(m, 2H), 7.08(m, 1H), 7.17(m, 1H), 7.34(s, 1H)

FAB (M+H): 219

48-2) 5-Chloromethyl-1-(3-methylbenzyl)imidazole hydrochloride

The title compound was obtained in a yield of 92% according to the sameprocedure as Preparation 28-2) except that the compound prepared inPreparation 48-1) was used as a starting material.

EXAMPLE 129 Synthesis of1-[1-(4-Methoxybenzyl)-1H-imidazol-5-yl]methyl-3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole(129)

62 mg(0.2 mmol) of the compound prepared in Example 114-2) was dissolvedin 2 ml of dimethylformamide, 26 mg(0.66 mmol) of sodium hydride wasadded thereto at 0° C., and the mixture was stirred for 5 minutes. 60mg(0.22 mmol) of the compound prepared in Preparation 43-2) was added tothe mixture, which was then stirred at room temperature for 5 hours. Thesolvent was removed by distillation under reduced pressure and 10 ml ofwater was added to the residue. The resulting mixture was extractedtwice with 10 ml of ethyl acetate, dried over anhydrous sodium sulfate,concentrated and subjected to silica gel column chromatography(eluent:dichloromethane/methanol=95/5, v/v) to obtain 77 mg(Yield 76%) of thetitle compound.

¹H NMR(CDCl₃) δ 2.41(m, 2H), 2.75(m, 1H), 3.03(m, 5H), 3.10(m, 1H),3.34(m, 1H), 3.76(m, 3H), 4.91(s, 2H), 4.93(s, 2H), 6.62 (d, 1H),6.82(d, 2H), 6.90-7.07(m, 3H), 7.21(s, 1H), 7.32(m, 1H), 7.43(m, 2H),7.60(s, 1H), 7.74(d, 1H), 7.82(d, 1H), 8.08(d, 1H)

FAB (M+H): 509, C31H32H4O3

EXAMPLE 130 Synthesis of1-[1-(4-Methoxybenzyl)-1H-imidazol-5-yl]methyl-3-(4-methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(130)

64 mg(0.2 mmol) of the compound prepared in Example 125-1) was dissolvedin 2 ml of dimethylformamide, 26 mg(0.66 mmol) of sodium hydride wasadded thereto at 0° C., and the mixture was stirred for 5 minutes. 60mg(0.22 mmol) of the compound prepared in Preparation 43-2) was added tothe mixture, which was then stirred at room temperature for 5 hours. Thesolvent was removed by distillation under reduced pressure and 10 ml ofwater was added to the residue. The resulting mixture was extractedtwice with 10 ml of ethyl acetate, dried over anhydrous sodium sulfate,concentrated and subjected to silica gel column chromatography(eluent:dichloromethane/methanol=90/10, v/v) to obtain 79 mg(Yield 80%) of thetitle compound.

¹H NMR(CDCl₃) δ 1.06(br, 2H), 1.72(m, 2H), 1.82(s, 3H), 2.86(br, 2H),3.28(br, 2H), 3.75(s, 3H), 4.91(s, 2H), 4.93(s, 2H), 6.63(d, 1H),6.82(d, 2H), δ 90-7.07(m, 3H), 7.23(s, 1H), 7.33(m, 1H), 7.44(m, 2H),7.61(s, 1H), 7.75(d, 1H), 7.82(d, 1H), 8.08(d, 1H)

FAB (M+H): 520, C32H33N5O2

EXAMPLE 131 Synthesis of1-[1(3-Chlorobenzyl)-1H-imidazol-5-yl]methyl-3-(4-methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(131)

64 mg(0.2 mmol) of the compound prepared in Example 125-1) was dissolvedin 2 ml of dimethylformamide, 26 mg(0.66 mmol) of sodium hydride wasadded thereto at 0° C., and the mixture was stirred for 5 minutes. 61mg(0.22 mmol) of the compound prepared in Preparation 44-2) was added tothe mixture, which was then stirred at room temperature for 5 hours. Thesolvent was removed by distillation under reduced pressure and 10 ml ofwater was added to the residue. The resulting mixture was extractedtwice with 10 ml of ethyl acetate, dried over anhydrous sodium sulfate,concentrated and subjected to silica gel column chromatography(eluent:dichloromethane/methanol=90/10, v/v) to obtain 75 mg(Yield 71%) of thetitle compound.

¹H NMR(CDCl₃) δ 1.02(br, 2H), 1.78(br, 2H), 1.87(s, 3H), 2.84(br, 2H),3.30(br, 2H), 6.64(m, 2H), 7.01(s, 1H), 7.10-7.30(m, 4H), 7.31-7.47(m,4H), 7.53(s, 1H), 7.73(d, 1H), 781(d, 1H), 7.96(d, 1H)

FAB (M+H): 524, C31H30N5OCl

EXAMPLE 132 Synthesis of1-[1-(3-Chlorobenzyl)-1H-imidazol-5-yl]#methyl-3-[N-(2-methoxyethyl)-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole(132)

62 mg(0.2 mmol) of the compound prepared in Example 114-2) was dissolvedin 2 ml of dimethylformamide, 26 mg(0.66 mmol) of sodium hydride wasadded thereto at 0° C., and the mixture was stirred for 5 minutes. 61mg(0.22 mmol) of the compound prepared in Preparation 44-2) was added tothe mixture, which was then stirred at room temperature for 5 hours. Thesolvent was removed by distillation under reduced pressure and 10 ml ofwater was added to the residue. The resulting mixture was extractedtwice with 10 ml of ethyl acetate, dried over anhydrous sodium sulfate,concentrated and subjected to silica gel column chromatography(eluent:dichloromethane/methanol=95/5, v/v) to obtain 80 mg(Yield 78%) of thetitle compound.

¹H NMR(CDCl₃) δ 2.39(br, 2H), 2.71(m, 1H), 3.02(br, 4H), 3.09(br, 1H),3.32(br, 1H), 4.09(br, 1H), 4.97(s, 2H), 5.04(s, 2H), 6.64(d, 1H),6.90(m, 1H), 7.02(d, 2H), 7.20-7.40(m, 4H), 7.40-7.60(m, 3H), 7.74(d,1H), 7.76(d, 1H), 7.85(s, 1H), 8.04(d, 1H)

FAB (M+H): 513, C30H29N4O2Cl

EXAMPLE 133 Synthesis of1-[1-(2-Chlorobenzyl)-1H-imidazol-5-yl]methyl-3-(4-methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(133)

64 mg(0.2 mmol) of the compound prepared in Example 125-1) was dissolvedin 2 ml of dimethylformamide, 26 mg(0.66 mmol) of sodium hydride wasadded thereto at 0° C., and the mixture was stirred for 5 minutes. 61mg(0.22 mmol) of the compound prepared in Preparation 45-2) was added tothe mixture, which was then stirred at room temperature for 5 hours. Thesolvent was removed by distillation under reduced pressure and 10 ml ofwater was added to the residue. The resulting mixture was extractedtwice with 10 ml of ethyl acetate, dried over anhydrous sodium sulfate,concentrated and subjected to silica gel column chromatography(eluent:dichloromethane/methanol-90/10, v/v) to obtain 80 mg(Yield 76%) of thetitle compound.

¹H NMR(CDCl₃) δ 1.06(br, 2H), 1.80(br, 2H), 1.86(s, 3H), 2.84(br, 2H),3.30(br, 2H), 4.98(s, 2H), 5.1 l(s, 2H), 6.63(m, 2H), 7.01(s, 1H),7.12-7.30 (m, 4H), 7.32-7.46(m, 4H), 7.53(s, 1H), 7.73(d, 1H), 7.81(d,1H), 7.97(d, 1H)

FAB (M+H): 524, C31H30N5OCl

EXAMPLE 134 Synthesis of1-[1-(2-Chlorobenzyl)-1H-imidazol-5-yl]methyl-3-[N-(2-methoxyethyl-N-methyl]carbamoyl-4-(naphthalen-1-yl)-1H-pyrrole(134)

62 mg(0.2 mmol) of the compound prepared in Example 114-2) was dissolvedin 2 ml of dimethylformamide, 26 mg(0.66 mmol) of sodium hydride wasadded thereto at 0° C., and the mixture was stirred for 5 minutes. 61mg(0.22 mmol) of the compound prepared in Preparation 45-2) was added tothe mixture, which was then stirred at room temperature for 5 hours. Thesolvent was removed by distillation under reduced pressure and 10 ml ofwater was added to the residue. The resulting mixture was extractedtwice with 10 ml of ethyl acetate, dried over anhydrous sodium sulfate,concentrated and subjected to silica gel column chromatography(eluent:dichloromethane/methanol=95/5, v/v) to obtain 77 mg(Yield 75%) of thetitle compound.

¹H NMR(CDCl₃) δ 2.37(br, 2H), 2.72(m, 1H), 3.01(br, 4H), 3.10(br, 1H),3.32(br, 1H), 4.18(br, 1H), 5.04(s, 2H), 5.17(s, 2H), 6.65(d, 1H),6.76(d, 2H), 7.04(d, 1H), 7.13-7.35(m, 4H), 7.36-7.50(m, 4H), 7.71(s,1H), 7.75(d, 1H), 7.82(d, 1H), 8.01(d, 1H)

FAB (M+H): 513, C30H29N4OCl

EXAMPLE 135 Synthesis of1-[1-(2-Fluorobenzyl)-1H-imidazol-5-yl]methyl-3-(4-methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(135)

64 mg(0.2 mmol) of the compound prepared in Example 125-1) was dissolvedin 2 ml of dimethylformamide, 26 mg(0.66 mmol) of sodium hydride wasadded thereto at 0° C., and the mixture was stirred for 5 minutes. 51mg(0.22 mmol) of the compound prepared in Preparation 46-2) was added tothe mixture, which was then stirred at room temperature for 5 hours. Thesolvent was removed by distillation under reduced pressure and 10 ml ofwater was added to the residue. The resulting mixture was extractedtwice with 10 ml of ethyl acetate, dried over anhydrous sodium sulfate,concentrated and subjected to silica gel column chromatography(eluent:dichloromethane/methanol=90/10, v/v) to obtain 79 mg(Yield 77%) of thetitle compound.

¹H NMR(CDCl₃) δ 1.06(br, 2H), 1.80(br, 2H), 1.86(s, 3H), 2.93(br, 2H),3.35(br, 2H), 5.03(s, 2H), 5.06(s, 2H), 6.66(m, 2H), 6.87(m, 1H),7.12-7.30 (m, 4H), 7.32-7.46(m, 4H), 7.58(s, 1H), 7.77(d, 1H), 7.82(d,1H), 7.97(d, 1H)

FAB (M+H): 508, C31H30N5OF

EXAMPLE 136 Synthesis of1-[1-(4-Methylbenzyl)-1H-imidazol-5-yl]methyl-3-(4-methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(136)

64 mg(0.2 mmol) of the compound prepared in Example 125-1) was dissolvedin 2 ml of dimethylformamide, 26 mg(0.66 mmol) of sodium hydride wasadded thereto at 0° C., and the mixture was stirred for 5 minutes. 57mg(0.22 mmol) of the compound prepared in Preparation 47-2) was added tothe mixture, which was then stirred at room temperature for 5 hours. Thesolvent was removed by distillation under reduced pressure and 10 ml ofwater was added to the residue. The resulting mixture was extractedtwice with 10 ml of ethyl acetate, dried over anhydrous sodium sulfate,concentrated and subjected to silica gel column chromatography(eluent:dichloromethane/methanol=90/10, v/v) to obtain 81 mg(Yield 80%) of thetitle compound.

¹H NMR(CDCl₃) δ 1.09(br, 2H), 1.83(br, 2H), 1.86(s, 3H), 2.24(s, 3H),2.93(br, 2H), 3.30(br, 2H), 4.86(s, 214), 4.91(s, 2H), 6.59(d, 1H),6.87(m, 2H), 7.01(s, 1H), 7.07(d, 2H), 7.15(s, 1H), 7.25(m, 1H), 7.50(m,3H), 7.53(s, 1H), 7.73(d, 1H), 7.78(d, 1H), 7.97(d, 1H)

FAB (M+H): 504, C32H33N5O

EXAMPLE 137 Synthesis of1-[1-(4-Methylbenzyl)-1H-imidazol-5-yl]methyl-3-(morpholin₄-yl)carbonyl-4-(naphthalen-1-yl-1H-pyrrole(137)

62 mg(0.2 mmol) of the compound prepared in Example 106-3) was dissolvedin 2 ml of dimethylformamide, 26 mg(0.66 mmol) of sodium hydride wasadded thereto at 0° C., and the mixture was stirred for 5 minutes. 57mg(0.22 mmol) of the compound prepared in Preparation 47-2) was added tothe mixture, which was then stirred at room temperature for 5 hours. Thesolvent was removed by distillation under reduced pressure and 10 ml ofwater was added to the residue. The resulting mixture was extractedtwice with 10 ml of ethyl acetate, dried over anhydrous sodium sulfate,concentrated and subjected to silica gel column chromatography(eluent:dichloromethane/methanol=95/5, v/v) to obtain 80 mg(Yield 81%) of thetitle compound.

1H NMR(CDCl₃) δ 2.29(s, 3H), 2.30-3.60(br, 8H), 4.94(s, 1H), 4.99(s,2H), 6.61(d, 1H), 6.91(d, 1H), 7.07(d, 1H), 7.12(d, 2H), 7.21(s, 1H),7.32(d, 1H), 7.35-7.50(m, 4H), 7.71(s, 1H), 7.77(d, 1H), 7.84(d, 1H),7.98(d, 1H)

FAB (M+H): 491, C31H30N4O2

EXAMPLE 138 Synthesis of1-[1-(3-Methylbenzyl)-1H-imidazol-5-yl]methyl-3-(4-methylpiperazin-1-yl)carbonyl-4-(naphthalen-1-yl)-1H-pyrrole(138)

64 mg(0.2 mmol) of the compound prepared in Example 125-1) was dissolvedin 2 ml of dimethylformamide, 26 mg(0.66 mmol) of sodium hydride wasadded thereto at 0° C., and the mixture was stirred for 5 minutes. 57mg(0.22 mmol) of the compound prepared in Preparation 48-2) was added tothe mixture, which was then stirred at room temperature for 5 hours. Thesolvent was removed by distillation under reduced pressure and 10 ml ofwater was added to the residue. The resulting mixture was extractedtwice with 10 ml of ethyl acetate, dried over anhydrous sodium sulfate,concentrated and subjected to silica gel column chromatography(eluent:dichloromethane/methanol=90/10, v/v) to obtain 74 mg(Yield 73%) of thetitle compound.

¹H NMR(CDCl₃) δ 1.06(br, 2H), 1.80(br, 2H), 1.84(s, 3H), 2.91(br, 2H),3.27(br, 2H), 4.86(s, 2H), 4.89(s, 2H), 6.57(d, 1H), 6.71(d, 1H), 6.77(s, 1H), 6.97(s, 1H), 7.01(d, 1H), 7.15(m, 2H), 7.25(d, 1H), 7.37(m,3H), 7.51(s, 1H), 7.70(d, 1H), 7.72(d, 1H), 7.98(d, 1H)

FAB (M+H): 504, C32H33N5O

Preparation 49 Synthesis of 3-(Naphthalen-1-yl)carbonyl-1H-pyrrole

49-1) Methyl N-methyl-1-naphthalen hydroxamate

3.44 g(20 mmol) of 1-naphthoic acid was dissolved in 20 ml ofdimethylformamide, and then 4.6 g(24 mmol) of EDC, 2.02 g(20 mmol) oftriethylamine and 3.24 g(24 mmol) of HOBT were added thereto. Theresulting mixture was stirred at 0° C. for 5 minutes. To the reactionsolution was added 1.85 g(20 mmol) of N,O-dimethylhydroxylaminehydrochloride, which was then stirred at room temperature for 5 hours.The solvent was removed under reduced pressure and then 100 ml ofsaturated potassium carbonate solution was added to the residue. Theresulting solution was extracted with ethyl acetate. Then, the organiclayer was washed sequentially with 1N aqueous hydrochloric acidsolution, aqueous sodium chloride solution and water, dried overanhydrous sodium sulfate and concentrated to give 3.04 g(1.50 mmol) ofthe title compound.

¹H NMR(CDCl₃) δ 2.42(s, 3H), 3.24(s, 3H), 7.47(m, 4H), 7.67(d, 1H),7.74(m, 2H),

FAB 216 (M+H)

49-2) 1-(Naphthalen-1-yl)-prop-2-en-1-one

2.03 g(9.4 mmol) of the compound prepared in Preparation 49-1) wasdissolved in 20 ml of dry tetrahydrofuran, and then 20 ml of 1Nvinylmagnesiumbromide-tetrahydrofuran solution was added slowly theretoat 0° C. The mixture was stirred at room temperature for 30 minutes and20 ml of 1N hydrochloric acid was added thereto, and then the resultingsolution was extracted with 50 ml of ethyl acetate. The organic layerwas dried over anhydrous magnesium sulfate and the solvent was removedunder reduced pressure to give 1.63 g(9 mmol; Yield 96%) of the titlecompound.

¹H NMR(CDCl₃) δ 6.92(m, 1H), 7.51(m, 4H), 7.74(d, 1H), 7.85(m, 2H),7.98(d, 1H), 8.31(d, 1H)

49-3) 3-(Naphthalen-1-yl)carbonyl-1H-pyrrole

901 mg(5 mmol) of the compound prepared in Preparation 49-2) and 1.01g(5.5 mmol) of tosylmethylisocyanide were dissolved in 10 ml oftetrahydrofuran. 555 mg(5.5 mmol) of potassium t-butoxide dissolved in10 ml of tetrahydrofuran was slowly added thereto and the mixture wasstirred for 30 minutes. 10 ml of water was added to the reactionsolution to stop the reaction and the solvent was removed under reducedpressure. 20 ml of water was added to the residue and the resultingmixture was extracted with ethyl acetate, washed with aqueous sodiumchloride solution and then dried over anhydrous magnesium sulfate. Thesolvent was removed under reduced pressure and the residue was subjectedto silica gel column chromatography(eluent: ethyl acetate/hexane=1/3,v/v) to obtain 884 mg(4 mmol, Yield 80%) of the title compound.

¹H NMR(CDCl₃) δ 6.57(s, 1H), 6.66(s, 1H), 6.79(s, 1H), 7.36(m, 3H),7.48(d, 1H), 7.77(d, 1H), 7.82(d, 1H), 8.04(d, 1H), 9.91(s, 1H)

Preparation 50 Synthesis of4-(Naphthalen-1-yl)carbonyl-3-[N-(2-methoxyethyl)-N-methylcarbamoyl)-1-1H-pyrrole

50-1) 4Naphthalen-1-yl)-4-oxo-2-butenoic acid

5.88 g(60 mmol) of dry maleic acid was dissolved in 100 ml of drytetrahydrofuran and the mixture was cooled down to 78° C. 4.14 g(20mmol) of 1-bromonaphthalene was dissolved in 100 ml of drytetrahydrofuran and 13.8 ml of 1.6N n-butyllithium-hexane solution wasadded thereto at 78° C. This reaction solution was stirred for 5 minutesand then it was added to the dry maleic acid solution prepared inadvance using cannula. The resulting mixture was stirred for 10 minutes,and water was added thereto to stop the reaction. The solvent wasremoved under reduced pressure, and the residue was acidified by 1Naqueous hydrochloric acid solution and extracted with ethyl acetate. Theorganic layer was washed with water and aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate, concentrated underreduced pressure and subjected to column chromatography(eluent: ethylacetate/hexane=2/1, v/v) to give 1.35 g(6.0 mmol; Yield 30%) of thetitle compound.

¹H NMR(CDCl₃) δ 6.81(d, 1H), 7.52-7.65(m, 3H), 7.85(d, 1H), 7.89(d, 1H),7.92(d, 1H), 8.06(d, 1H), 8.56(d, 1H)

50-2)N-(2-methoxyethyl)-N-methyl-4-(naphthalen-1-yl)-4-oxo-2-butenoamide

1.3 g(5.9 mmol) of the compound prepared in Preparation 50-1) wasdissolved in 10 ml of dimethylformamide, and then 1.7 g(8.9 mmol) of EDCand 1.2 g(8.9 mmol) of HOBT were added thereto at 0° C. The resultingmixture was stirred for 5 minutes. To the reaction solution were added530 mg(5.9 mmol) of N-(2-methoxyethyl)-N-methylamine and 1.2 ml(8.9mmol) of triethylamine, the mixture of which was then stirred at roomtemperature for 2 hours. The solvent was removed under reduced pressureand then 50 ml of water was added to the residue. The resulting solutionwas extracted with ethyl acetate. The organic layer was washed withaqueous sodium chloride solution, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue was subjected tocolumn chromatography(eluent: ethyl acetate/hexane=1/1, v/v) to give 1.4g(4.7 mmol; Yield 80%) of the title compound.

¹H NMR(CDCl₃) δ 3.05(s, 3H), 3.32(s, 3H), 3.54(m, 2H), 3.65(m, 2H),7.40-7.58(m, 4H), 7.71(t, 1H), 7.89(m, 2H), 8.03(d, 1H), 8.54(d, 1H)

50-3)3-[N-(2-methoxyethyl)-N-methyl]carbamoyl)-4-(naphthalen-1-yl)carbonyl-1H-pyrrole

1.4 g(4.7 mmol) of the compound prepared in Preparation 50-2) and 1.0g(5.1 mmol) of tosylmethylisocyanide were dissolved in 20 ml oftetrahydrofuran. 790 mg(7.0 mmol) of potassium t-butoxide was addedthereto and the mixture was stirred at room temperature for 3 hours. 2ml of water was added to the reaction solution to stop the reaction andthe solvent was removed under reduced pressure. The residue wasextracted with ethyl acetate, washed with aqueous sodium chloridesolution and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure and the residue was subjected to columnchromatography(eluent: ethyl acetate/hexane=2/3, v/v) to give 1.2 g(3.6mmol, Yield 76%) of the title compound.

¹H NMR(CDCl₃) δ 3.04(s, 3H), 3.35(s, 3H), 3.47(m, 2H), 3.64(m, 2H),6.55(d, 1H), 6.63(m, 1H), 7.21-7.40(m, 4H), 7.74(m, 2H), 8.00(m, 1H),11.4 (br, 1H)

EXAMPLE 139 Synthesis of1-[1-(4-Cyanobenzyl)-1H-imidazol-5-yl]methyl-3-(naphthalen-1-yl)carbonyl-1H-pyrrole(139)

The title compound was obtained in a yield of 35% according to the sameprocedure as Example 1 except that the compound prepared in Preparation29-5) and the compound prepared in Preparation 49-3) were used.

¹H NMR(CDCl₃) δ 4.86(s, 2H), 4.95(s, 2H), 6.52(s, 1H), 6.61(s, 1H),6.89(m, 3H), 7.20(s, 1H), 7.49(m, 6H), 7.75(s, 1H), 7.87(d, 1H), 7.95(d,1H), 8.11(d, 1H)

FAB: 417 (M+1)

EXAMPLE 140 Synthesis of1-[1-(4-Bromobenzyl)-1H-imidazol-5-yl]methyl-3-(naphthalen-1-yl)carbonyl-1H-pyrrole(140)

The title compound was obtained in a yield of 20% according to the sameprocedure as Example 1 except that the compound prepared in Preparation32-2) and the compound prepared in Preparation 49-3) were used.

¹H NMR(CDCl₃) δ 4.84(s, 2H), 4.92(s, 2H), 6.54(s, 1H), 6.67(s, 1H),6.78(d, 2H), 6.93(s, 1H), 7.22(s, 1H), 7.38(d, 2H), 7.50(m, 3H), 7.58(d,1H), 7.89(d, 1H), 7.95(d, 1H), 8.13(d, 1H), 8.16(s, 1H)

FAB 470 (M+1)

EXAMPLE 141 Synthesis of1-[1-(4-Bromobenzyl)-1H-imidazol-5-yl]methyl-3-[N-(2-methoxyethyl)-N-methyl]carbamoyl(naphthalen-1-yl)carbonyl-1H-pyrrole(141)

The title compound was obtained in a yield of 81% according to the sameprocedure as Example 1 except that the compound prepared in Preparation32-2) and the compound prepared in Preparation 50-3) were used.

¹H NMR(CDCl₃) δ 2.94(s, 3H), 3.25(s, 3H), 3.42(m, 2H), 3.48(m, 2H), 4.72(s, 2H), 4.78(s, 2H), 6.64(m, 4H), 7.28-7.48(m, 8H), 7.81 (m, 2H),8.14(m, 1H)

FAB: 585 (M+1)

Preparation 51 Synthesis of Ethyl 1-Naphthoylglycinate Hydrochloride

51-1) Ethyl N-(diphenylmethylene)glycinate

Glycine ethylester hydrochloride salt and diphenylketimine were reactedaccording to the procedure described in M. J. O'Donnell, R. L. Polt, J.Org. Chem 47, 2663, 1982 to give the title compound in a yield of 90%.

¹H NMR(CDCl₃) δ 1.20(t, 3H), 4.12(m, 4H), 7.10-7.40(m, 8H), 7.59(d, 2H)

51-2) Ethyl 1-naphthoylglycinate hydrochloride

1-Naphthoylchloride and the compound prepared in Preparation 51-1) werereacted according to the procedure described in J. Singh, et. al.Tetrahedron Left., 34(2), 211, 1993 to give the title compound in ayield of 48%.

¹H NMR(DMSO-d6) δ 1.78(s, 3H), 3.65(q, 1H), 3.95-4.15(m, 2H), 6.33(s,1H), 7.58-7.85(m, 3H), 8.15(d, 1H), 8.31(d, 1H), 8.38(d, 2H), 8.42(d,2H)

Preparation 52 Synthesis of2-[1-(4-Chlorobenzyl)-1H-imidazol-5-yl]thioacetamide

52-1) 1-(4-Chlorobenzyl)-5-hydroxymethyl-1H-imidazole

The title compound was obtained in a yield of 50% according to thesimilar procedure described in J. M. Dener, L-H Zhang, H. Rapoport, J.Org. Chem., 1993, 58, 1159 using dihydroxyacetone dimer and4-chlorobenzylamine hydrochloride as starting materials.

¹H NMR(CDCl₃+CD₃OD) δ 4.50(s, 2H), 5.20(s, 2H), 6.94(s, 1H), 7.06(d,2H), 7.32(d, 2H), 7.46(s, 1H)

52-2) 1-(4-Chlorobenzyl)-5-chloromethyl-1H-imidazole hydrochloride

3.00 g(13.5 mmol) of the compound prepared in Preparation 52-1) wasdissolved in 40 ml of chloroform, 2.88 ml(40.5 mmol) of thionylchloridewas slowly added thereto at 0° C., and the mixture was stirred at roomtemperature for 2 hours. The organic solvent was removed under reducedpressure to give 3.64 g(13.1 mmol, Yield 97%) of the title compound.This compound was used directly in the next reaction withoutpurification.

52-3) [1-(4-Chlorobenzyl)-1H-imidazol-5-yl]acetonitrile

1.2 g(4.3 mmol) of the compound prepared in Preparation 52-2) wasdissolved in 10 ml of dimethylsulfoxide and 1.3 g(26 mmol) ofsodiumcyanide was added thereto. The mixture was stirred at roomtemperature for 6 hours. 30 ml of water was added thereto and theresulting mixture was extracted with ethyl acetate(20 ml×3). The organiclayer was dried over anhydrous sodium sulfate and concentrated to give0.96 g(4.1 mmol, Yield 96%) of the title compound. This compound wasused in the next reaction without purification.

¹H NMR(CDCl₃) δ 3.70(s, 2H), 5.12(s, 2H), 6.88(s, 1H), 7.34(d, 2H),7.62(d, 2H), 771(s, 1H)

52-4) 2-[1-(4-Chlorobenzyl)-1H-imidazol-5-yl]thioacetamide

150 mg(0.64 mmol) of the compound prepared in Preparation 52-3) wasdissolved in a solvent mixture of 1 ml of pyridine and 0.3 ml oftriethylamine and then saturated by bubbling hydrogen sulfide gasthrough the solution for 30 minutes. The reaction solution was stirredat room temperature for 12 hours. The solvent was removed under reducedpressure and 10 ml of water was added thereto. The mixture was extractedwith 10 ml of ethyl acetate. The organic layer was dried over anhydroussodium sulfate, concentrated and subjected to silica gel columnchromatography (eluent: methylene chloride/methanol=20/1, v/v) to give110 mg(0.41 mmol, Yield 64%) of the title compound.

¹H NMR(CDCl₃+CD₃OD) δ 3.21(s, 2H), 5.05(s, 2H), 6.76(s, 1H), 7.24(d,2H), 7.61(d, 2H), 7.67(s, 1H)

FAB:266(M+1)

Preparation 53 Synthesis of2-{1-[1-(Benzyloxycarbonyl)piperidin-4-yl]methyl-1H-imidazol-5-yl}thioacetamide

53-1) 4-Aminomethyl-1-(benzyloxycarbonyl)piperidine

22.2 g(0.2 mol) of 4-aminomethylpiperidine was dissolved in 250 ml oftoluene and 21.2 g(0.2 mol) of benzaldehyde was added thereto. Thereaction mixture was refluxed for 3 hours with Dean-stack to removewater, and then cooled down to 0° C. 34.2 g(0.2 mol) ofbenzylchloroformate was added slowly thereto while sting. The mixturewas stirred at room temperature for 3 hours and 220 ml of 1N aqueousKHSO₄ solution was added thereto. The mixture was extracted three timeswith 200 ml of diethylether, and the aqueous layer was basified with 1Naqueous sodium hydroxide solution. The aqueous solution was saturatedwith sodium chloride. The aqueous layer was extracted three times with100 ml of dichloromethane, dried over anhydrous magnesium sulfate anddistilled under reduced pressure to give 38 g(Yield 91% Molecular weight248) of the title compound.

¹H NMR(CDCl₃) δ 1.11(s, 2H), 1.49(s, 3H), 1.70(d, 2H), 2.57(d, 2H)2.78(s, 2H), 4.20(s, 2H). 5.12(s, 2H), 7.34-7.35(m, 5H)

53-2)1-[1-(Benzyloxycarbonyl)piperidin-4-ylmethyl-5-hydroxymethyl-2-mercapto-1H-imidazole

24.8 g(0.1 mol) of the compound prepared in Preparation 53-1) and 6.0g(0.1 mol) of acetic acid were dissolved in 50 ml of n-butanol, asolution wherein 12.6 g(0.13 mol) of potassium thiocyanate, 15.2 g(0.1mol) of 1,3-dihydroxyacetone dimer and 10.0 g(0.17 mol) of acetic acidwere dissolved in 50 ml of n-butanol was added thereto, and the wholemixture was stirred at room temperature. After 48 hours, the solvent wasremoved by distillation under reduced pressure, and then the residue wasdissolved in 200 ml of ethyl acetate and washed three times with 100 mlof water. The organic layer was dried over anhydrous magnesium sulfateand concentrated to give 27 g(75 mmol, Yield 75%) of the title compound.

¹H NMR(CDCl₃) δ 1.22(d, 2H), 1.57(d, 2H), 2.30(s, 1H), 2.72(s, 2H),3.96(s, 2H), 4.15(d, 2H), 4.46(s, 2H), 5.10(s, 2H), 6.62(s, 1H),7.26-7.37(m, 5H)

53-3)1-[1-(Benzyloxycarbonyl)piperidin₄-yl]methyl-5-hydroxymethyl-1H-imidazole

18.05 g(50 mmol) of the compound prepared in Preparation 53-2) was addedto a mixture of 100 ml of 10% nitric acid and 10 ml of ethyl acetate,the reaction mixture was cooled with cold ice water and then stirred atroom temperature for 3 hours. The mixture was basified using 4N aqueoussodium hydroxide solution and extracted twice with 100 ml of ethylacetate. The extracted organic solution was dried over magnesium sulfateand distilled under reduced pressure to give 12.3 g(38 mmol, Yield 75%)of the title compound.

¹H NMR(CDCl₃) δ 1.16(d, 2H), 1.56(d, 2H), 1.98(s, 1H), 2.70(s, 2H),3.88(d, 2H), 4.18(s, 2H), 4.49(s, 1H), 4.56(s, 3H), 5.10(s, 2H), 6.82(s,1H), 7.27-7.40(m, 6H)

53-4)1-[1-(Benzyloxycarbonyl)piperidin-4-yl]methyl-5-chloromethyl-1H-imidazolehydrochloride

9.9 g(30 mmol) of the compound prepared in Preparation 53-3) wasdissolved in 50 ml of chloroform, and 7.1 g(60 mmol) of thionylchloridewas slowly added thereto at 0° C. The reaction solution was stirred for2 hours and the solvent was removed by distillation under reducedpressure to give 9.9 g(Yield 95%, Molecular weight 347.5) ofhydrochloride salt of the title compound. This compound was useddirectly in the next reaction without purification.

53-5){1-[1-(Benzyloxycarbonyl)piperidin-4-yl]methyl-1H-imidazol-5-yl}acetonitrile

The title compound was obtained in a yield of 39% according to thesimilar procedure as Preparation 52-3) using the compound prepared inPreparation 53-4).

¹H NMR(CDCl₃) δ 1.19(br, 2H), 1.60(br, 2H), 1.90(m, 1H), 2.72(br, 2H),3.71(s, 2H), 3.81(d, 2H), 4.22(br, 2H), 5.11(s, 2H), 7.03(s, 1H),7.29-7.36(m, 5H), 7.51(s, 1H)

53-6)2-{1-[1-(Benzyloxycarbonyl)piperidin-4-yl]methyl-1H-imidazol-5-yl}thioacetamide

The title compound was obtained in a yield of 74% according to thesimilar procedure as Preparation 52-4) using the compound prepared inPreparation 53-5).

¹H NMR(CDCl₃) δ 1.21(br, 2H), 1.63(br, 2H), 1.87(m, 1H), 2.71(br, 2H),3.31 (s, 2H), 3.84(d, 2H), 4.25(br, 2H), 5.12(s, 2H), 7.10(s, 1H),7.33-7.41(m, 5H), 7.62(s, 1H)

FAB: 373 (M+1)

Preparation 54 Synthesis of Methyl3-Chloro-3-(naphthalen-1-yl)-2-oxopropionate

7.80 g(49.9 mmol) of 1-naphthaldehyde and 7.15 g(49.9 mmol) of methyldichloroacetate were dissolved in 100 ml of t-butanol, and 6.15 g(54.8mmol) of potassium t-butoxide was added thereto at 0° C. The mixture wasstirred at room temperature for 24 hours and then 50 ml of water wasadded to stop the reaction. The solvent was removed under reducedpressure and the residue was extracted with ethyl acetate, The organiclayer was dried over magnesium sulfate, concentrated and subjected tosilica gel column chromatography(eluent: n-hexane/ethyl acetate=90/10,v/v) to give 2.5 g(9.52 mmol, Yield 19%) of the title compound.

¹H NMR(CDCl₃) δ 3.78(s, 3H), 6.92(s, 1H), 7.45-7.73(m, 4H), 7.95(m, 2H),8.12(d, 1H)

Preparation 55 Synthesis of Methyl2-Chloro-3-(naphthalen-1-yl)-3-oxopropionate

55-1) Methyl 3-(naphthalen-1-yl)-3-oxopropionate

10.2 g(59.9 mmol) of 1-acetonaphthone and 4.8 g(60% in mineral oil, 120mmol) of sodium hydride were added to 100 ml of dimethylcarbonate andthe mixture was refluxed for 24 hours. The solvent was removed underreduced pressure, 100 mg of 1N aqueous HCl solution was added to theresidue, and the resulting mixture was extracted with 100 ml of ethylacetate. The organic layer was washed with water(100 ml×3), dried overanhydrous magnesium sulfate and concentrated. The residue was subjectedto silica gel column chromatography(eluent: n-hexane/ethylacetate=90/10, v/v) to give 10.0 g (43.8 mmol, Yield 73%) of the titlecompound.

¹H NMR(CDCl₃) δ 3.75(s, 3H), 4.14(s, 2H), 7.45-7.68(m, 3H), 7.82-8.08(m,3H), 8.77(d, 1H)

55-2) Methyl 2-chloro-3-(naphthalen-1-yl)-3-oxopropionate

4.56 g(20.0 mmol) of the compound prepared in Preparation 55-1) wasdissolved in 50 ml of 1,2-dichloroethane, and 2.70 g(20.0 mmol) ofsulfuryl chloride was slowly added thereto at 0° C. The mixture wasstirred at room temperature for 3 hours. The solvent was removed bydistillation under reduced pressure to give 4.70 g(179 mmol, Yield 89%)of the title compound.

¹H NMR(CDCl₃) δ 3.75(s, 3H), 5.82(s, 2H), 7.50-7.72(m, 3H). 7.85-8.15(m,3H), 8.65(d, 1H)

EXAMPLE 142 Synthesis of4-Ethoxycarbonyl-2-(1H-imidazol-5-ylmethyl)-5-(naphthalen-1-yl)oxazole(142)

142-1) Ethyl2-[(1H-imidazol-5-yl)acetylamino]-3-(naphthalen-1-yl)-3-oxopropionate

293 mg(0.997 mmol) of the compound prepared in Preparation 51-2), 162mg(0.996 mmol) of 4-imidazoleacetic acid hydrochloride, 135 mg(0.999mmol) of HOBT and 191 mg(0.996 mmol) of EDC were added to 10 ml ofdimethylformamide, and then 202 mg(1.99 mmol) of triethylamine wasslowly added thereto while stirring. The mixture was stirred at roomtemperature for 5 hours and then the solvent therein was removed underreduced pressure. To the residue was added 30 ml of ethyl acetate, whichwas then washed with saturated sodium bicarbonate solution and water.The organic layer was dried over anhydrous magnesium sulfate,concentrated and subjected to silica gel column chromatography(eluent:dichloromethane/methanol=95/5, v/v) to give 200 mg(0.547 mmol, Yield55%) of the title compound.

¹H NMR(CDCl₃) δ 0.92(t, 3H), 3.70(s, 2H), 3.98-4.15(m, 2H), 6.20(d, 1H),6.92(s, 1H), 7.55(m, 4H), 7.65(s, 1H), 7.89(d, 1H), 8.06(d, 1H),8.12(br, 1H), 8.21(d, 1H), 8.45(d, 1H)

142-2)4-Ethoxycarbonyl-2-(1H-imidazol-5-ylmethyl)-5-(naphthalen-1-yl)oxazole

100 mg(0.27 mmol) of the compound prepared in Example 142-1) wasdissolved in 5 ml of THF and then refluxed for 6 hours. The solvent wasremoved by distillation under reduced pressure and the residue wassubjected to silica gel column chromatography(eluent:dichloromethane/methanol=95/5, v/v) to give 40 mg(0.12 mmol, Yield 44%)of the title compound.

¹H NMR(CDCl₃) δ 0.98(t, 3H), 4.13(q, 2H), 4.27(s, 2H), 6.92(s, 1H),7.45-7.58(m, 4H), 7.65-7.75(m, 2H), 7.89(d, 1H), 7.97(d, 1H)

FAB: 348 (M+1)

EXAMPLE 143 Synthesis of2-(1H)-imidazol-5-ylmethyl)-4-(morpholin-4-yl)carbonyl-5-(naphthalen-1-yl)oxazole(143)

31 mg(0.09 mmol) of the compound prepared in Example 142-2) wasdissolved in a solvent mixture of tetrahydrofuran/methanol/water(0.6ml/0.3 ml/1 ml), and 6 mg(0.13 mmol) of lithium hydroxide was addedthereto. The reaction solution was stirred at room temperature for 3hours, and the solvent was removed under reduced pressure. The residuewas adjusted to pH 6 using 0.1N aqueous hydrochloric acid solution andthen extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate and concentrated. The concentrate was dissolvedin 1 ml of dimethylformamide, 18 mg(0.13 mmol) of HOBT and 26 mg(0.13mmol) of EDC were added thereto at 0° C., and the mixture was stirredfor 10 minutes. 9 μl(0.09 mmol) of morpholine and 18 μg (0.13 mmol) oftriethylamine were added thereto and the mixture was stirred at roomtemperature for 2 hours. The reaction solution was treated according tothe same procedure as Example 142-1) to give 14 mg(0.04 mmol, Yield 45%)of the title compound.

¹H NMR(CDCl₃) δ 2.97(br, 2H), 3.24(br, 2H), 3.43(br, 2H), 3.57(br, 2H),4.27(s, 2H), 6.95(s, 1H), 7.52-7.67(m, 6H), 7.81-7.95(m, 3H)

FAB 389 (M+1)

EXAMPLE 144 Synthesis of4-Ethoxycarbonyl-2-(1H-imidazol-5-ylmethyl)-5-(naphthalen-1-yl)thiazole(144)

105 mg(0.287 mmol) of the compound prepared in Example 142-1) and 116mg(0.287 mmol) of Lawesson's Reagent were dissolved in 10 ml oftetrahydrofuran, and the mixture was refluxed for 6 hours. The solventwas removed under reduced pressure, 10 ml of saturated sodiumbicarbonate solution was added to the residue, and then the resultingmixture was extracted with ethyl acetate. The organic layer was driedover anhydrous magnesium sulfate, concentrated and subjected to silicagel column chromatography(eluent: dichloromethane/methanol=95/5, v/v) togive 26 mg(0.075 mmol, Yield 26%) of the compound of Example 142-2) and24 mg(0.066 mmol, Yield 23%) of the title compound.

¹H NMR(CDCl₃) δ 0.63(t, 3H), 3.92(q, 2H), 4.42(s, 2H), 6.97(s, 1H),7.405-7.75(m, 6H), 7.85-7.95(m, 2H)

FAB: 364 (M+1)

EXAMPLE 145 Synthesis of2-[1-(4-Chlorobenzyl)-1H-imidazol-5-ylmethyl]-4-methoxycarbonyl-5-(naphthalen-1-yl)thiazole(145)

130 mg(0.49 mmol) of the compound prepared in Preparation 52-4) and 129mg(0.49 mmol) of the compound prepared in Preparation 54 were dissolvedin 5 ml of ethanol, and the mixture was refluxed for 5 hours. Thesolvent was removed by distillation under reduced pressure and theresidue was subjected to silica gel column chromatography (eluent:dichloromethane/methanol=40/1, v/v) to give 45 mg(0.095 mmol, Yield 19%)of the title compound.

¹H NMR(CDCl₃) δ 3.50(s, 3H), 4.26(s, 2H), 5.1 l(s, 2H), 6.92(d, 2H),7.07(s, 1H), 7.21-7.43(m, 7H), 7.53(s,]H), 7.83(m, 2H)

FAB: 474 (M+1)

EXAMPLE 146 Synthesis of2-[1-(4-Chlorobenzyl)-1H-imidazol-5-ylmethyl]-4-(morpholin-4-yl)carbonyl-5-(naphthalen-1-yl)thiazole(146)

The title compound was obtained in a yield of 23% according to thesimilar procedure as Example 143 using the compound prepared in Example145.

¹H NMR(CDCl₃) δ 2.63(br, 2H), 3.02(br, 2H), 3.24(br, 2H), 3.42(br, 2H),4.26(s, 2H), 5.21(s, 2H), 7.02(m, 2H), 7.18(s, 1H), 7.31(m, 2H),7.43-7.60(m, 5H), 7.78-7.96(m, 3H)

FAB 529 (M+1)

EXAMPLE 147 Synthesis of2-[1-(4-Chlorobenzyl)-1H-imidazol-5-ylmethyl]-4-[N-(2-methoxy)ethyl-N-methylcarbamoyl]-5-(naphthalen-1-yl)thiazole(147)

The title compound was obtained in a yield of 41% according to thesimilar procedure as Example 143 using the compound prepared in Example145 except that N-(2-methoxyethyl)methylamine was used instead ofmorpholine

¹H H NMR(CDCl₃) δ 2.68(br, 3H), 2.89-3.39(m, 7H), 4.22(s, 2H), 5.17(s,2H), 7.01(m, 2H), 7.15(s, 1H), 7.33(m, 2H), 7.40-7.61 (m, 5H),7.71-7.82(m, 3H)

FAB: 531 (M+1)

EXAMPLE 148 Synthesis of2-[1-(4-chlorobenzyl)-1H-imidazol-5-ylmethyl]-5-methoxycarbonyl-4-(naphthalen-1-yl)thiazole(148)

250 mg(0.95 mmol) of the compound prepared in Preparation 52-4) and 249mg(0.95 mmol) of the compound prepared in Preparation 55-2) weredissolved in 10 ml of ethanol, and the mixture was refluxed for 24hours. The solvent was removed by distillation under reduced pressureand the residue was subjected to silica gel column chromatography(eluent: dichloromethane/methanol=40/1, v/v) to give 180 mg(0.38 mmol,Yield 40%) of the title compound.

¹H NMR(CDCl₃) δ 3.53(s, 3H), 4.22(s, 2H), 5.12(s, 2H), 6.91(m, 2H),7.11(s, 1H), 7.21-7.54(m, 7H), 7.83(m, 3H)

FAB: 474 (M+1)

EXAMPLE 149 Synthesis of2-[1-(4-Chlorobenzyl)-1H-imidazol-5-ylmethyl]-5-(morpholin-4-yl)carbonyl-4-(naphthalen-1-yl)thiazole(149)

The title compound was obtained in a yield of 39% according to thesimilar procedure as Example 143 using the compound prepared in Example148.

¹H NMR(CDCl₃) δ 2.38(br, 2H), 2.82(br, 2H), 3.21(br, 2H), 3.42(br, 2H),4.27(s, 2H), 5.21 (s, 2H), 6.98(m, 2H), 7.25(m, 3H), 7.50-7.61(m, 5H),7.89-7.99 (m, 3H)

FAB 529 (M+1)

EXAMPLE 150 Synthesis of2-{1-[1-(Benzyloxycarbonyl)piperidin-4-ylmethyl]-1H-imidazol-5-ylmethyl}-5-methoxycarbonyl-4-(naphthalen-1-yl)thiazole(150)

124 mg(0.33 mmol) of the compound prepared in Preparation 53-6) and 87mg(0.33 mmol) of the compound prepared in Preparation 55-2) weredissolved in 10 ml of ethanol, and the mixture was refluxed for 20hours. The solvent was removed by distillation under reduced pressureand the residue was subjected to silica gel column chromatography(eluent: dichloromethane/methanol=95/5, v/v) to give 95 mg(0.16 mmol,Yield 48%) of the title compound.

¹H NMR(CDCl₃) δ 1.10(br, 2H), 1.53(br, 3H), 2.50(br, 2H), 3,62(s, 3H),3.81(d, 2H), 4.19(br, 2H), 4.41(s, 2H), 5.14(d, 2H), 7.16(s, 1H),7.27-7.61(m, 10H), 7.78(s, 1H), 7.91(d, 1H), 7.96(d, 1H)

FAB: 595 (M+1)

EXAMPLE 151 Synthesis of2-{1-[1-(Benzyloxycarbonyl)piperidin-4-ylmethyl]-1H-imidazol-5-ylmethyl}-5[N-(2-methoxy)ethyl-N-methylcarbamoyl]-4-(naphthalen-1-yl)thiazole(151)

The title compound was obtained in a yield of 36% according to thesimilar procedure as Example 143 using the compound prepared in Example150 except that N-(2-methoxyethyl)methylamine was used instead ofmorpholine.

¹H NMR(CDCl₃) δ 2.68(br, 3H), 2.89-3.39(m, 7H), 4.22(s, 2H), 5.17(s,2H), 7.01(m, 2H), 7. 15(s, 1H), 7.33(m, 2H), 7.40-7.61(m, 5H),7.71-7.82(m, 3H)

FAB: 638 (M+1)

Preparation 56 Synthesis of4-(5-Chloromethyl-1H-imidazol-1-ylmethyl)piperidine-1-carboxylic AcidBenzylester

56-1) 4-Aminomethyl-piperidine-1-carboxylic acid benzylester

22.2 g(0.2 mol) of 4-aminomethyl-piperidine was dissolved in 250 ml oftoluene and then 21.2 g(0.2 mol) of benzaldehyde was added thereto. Themixture was refluxed for 3 hours with Dean-stack and cooled down to 0°C., and then 34.2 g(0.2 mol) of benzylchloroformate was added theretowhile stirring. After the mixture was stirred for 3 hours, 1N aqueouspotassium hydrosulfate solution(220 ml) was added thereto at roomtemperature. The mixture was extracted three times with 200 ml ofdiethylether, and then the aqueous layer was basified with sodiumhydroxide. The aqueous solution was saturated with sodium chloride andextracted three times with 100 ml of dichloromethane. The organicsolution was dried over magnesium sulfate and distilled under reducedpressure to obtain 38 g(Yield 91%, Molecular weight 248) of the titlecompound.

¹H NMR(CDCl₃) δ 1.11(s, 2H), 1.49(s, 3H), 1.70(d, 2H), 2.57(d, 2H),2.78(s, 2H), 4.20(s, 2H), 5.12(s, 2H), 7.34-7.35(m, 5H)

FAB (M+H): 249

56-2)4-(5-Hydroxymethyl-2-mercapto-1H-imidazol-1-ylmethyl)-piperidine-1-carboxylicacid benzylester

24.8 g(0.1 mol) of the compound prepared in Preparation 56-1) and 6.0g(0.1 mol) of acetic acid were dissolved in 50 ml of n-buthanol, andthen the resulting solution was added to a solution wherein 12.6 g(0.13mol) of potassium thiocyanate, 15.2 g(0.1 mol) of 1,3-dihydroxyacetonedimer and 10.0 g(0.17 mol) of acetic acid were dissolved in 50 ml ofn-butanol. The whole mixture was stirred for 48 hours. The solvent wasremoved by distillation under reduced pressure, 200 ml of ethyl acetatewas added thereto, and the mixture was washed three times with 100 ml ofwater. The organic layer was dried over magnesium sulfate, and thesolvent was removed by distillation under reduced pressure to obtain 27g(75 mmol, Yield 75%, Molecular weight 361) of the title compound.

¹H NMR(CDCl₃) δ 1.22(d, 2H), 1.57(d, 2H), 2.30(s, 1H), 2.72(s, 2H), 3.96(s, 2H), 4.15(d, 2H), 4.46(s, 2H), 5.10(s, 2H), 6.62(s, 1H),7.26-7.37(m, 5H)

FAB (M+H): 362

56-3) 4-(5-Hydroxymethyl-1H-imidazol-1-ylmethyl)-piperidine-1-carboxylicacid benzylester

18.05 g(50 mmol) of the compound prepared in Preparation 56-2) was addedto a mixture of 100 ml of nitric acid(10%) and 10 ml of ethyl acetate.The whole mixture was soaked in cold ice water for 5 minutes, andstirred at room temperature for 3 hours. The mixture was basified with4N aqueous sodium hydroxide solution, and then extracted twice with 100mg of ethyl acetate. The organic extract was dried over magnesiumsulfate and distilled under reduced pressure to obtain 12.3 g (38 mmol,Yield 75%, Molecular weight 329) of the title compound.

¹H NMR(CDCl₃) δ 1.16(d, 2H), 1.56(d, 2H), 1.98(s, 1H), 2.70(s, 2H), 3.88(d, 2H), 4.18(s, 2H), 4.49(s, 1H), 4.56(s, 3H), 5.10(s, 2H), 6.82(s,1H), 7.27-7.40 (m, 5H)

FAB (M+H): 330

56-4) 4-(5-Chloromethyl-1H-imidazol-1-ylmethyl)-piperidine-1-carboxylicacid benzylester

9.9 g(30 mmol) of the compound prepared in Preparation 56-3) wasdissolved in 50 ml of chloroform, and 7.1 g(60 mmol) of thionyl chloridewas slowly added thereto at 0° C. The mixture was stirred for 2 hours,the solvent was removed by distillation under reduced pressure, and theresidual hydrochloric acid was removed under vacuum to obtain 9.9g(Yield 95%, Molecular weight 347.5) of hydrochloric acid salt of thetitle compound.

¹H NMR(CDCl₃) δ 1.12(d, 2H), 1.53(d, 2H), 2.65(s, 2H), 3.82(d, 2H), 4.22(s, 2H), 4.42(s, 1H), 4.49(s, 3H), 5.12(s, 2H), 6.60(s, 1H),7.30-7.41(m, 5H)

FAB (M+H): 349

Preparation 57 Synthesis of1-(4-Chlorobenzyl)-5-chloromethyl-1H-imidazole Hydrochloride

57-1) 1-(4-Chlorobenzyl)-5-hydroxymethyl-1H-imidazole

The title compound was obtained in a yield of 50% according to theprocedure described in J. M. Dener, L-H Zhang, H. Rapoport, J. Org.Chem., 1993, 58, 1159 using dihydroxyacetone dimer and4-chlorobenzylamine hydrochloride as starting materials.

¹H NMR(CDCl₃+CD₃OD) δ 4.46(s, 2H), 5.26(s, 2H), 7.00(s, 1H), 7.07(d,2H), 7.50(d, 2H), 7.65(s, 1H)

57-2) 1-(4-Chlorobenzyl)-5-chloromethyl-1H-imidazole hydrochloride

The title compound was obtained in a yield of 96% according to thesimilar procedure as Preparation 56-4) except that the compound preparedin Preparation 57-1) was used as a starting material. This compound wasdirectly used in the next reaction without purification.

Preparation 58 Synthesis of4-[N-(2-methoxyethyl)-N-methyl]carbamoyl-3-(naphthalen-1-yl)-1H-pyrazole

58-1) N-t-Butyl-N′-(naphthalen-1-ylmethylenyl)-hydrazine

5.0 g(32 mmol) of 1-naphthaldehyde and 3.99 g(32 mmol) oft-butylhydrazine hydrochloride were dissolved in 100 ml of methanol, andthen the mixture was reacted with 1 ml of acetic acid at roomtemperature for 24 hours. After the solvent was removed by distillationunder reduced pressure, 20 ml of ethyl acetate was added to the residue.The mixture was washed with saturated sodium hydrogen carbonatesolution. Then, the separated organic layer was dried over anhydrousmagnesium sulfate and distilled under reduced pressure to remove thesolvent to obtain 6.3 g(28 mmol, Yield 86%) of the title compound.

¹H NMR(CDCl₃) δ 1.70(s, 9H), 7.23(s, 1H), 7.32(m, 1H), 7.42(m, 2H), 7.80(d, 1H), 7.90(d, 2H), 8.60(d, 1H), 9.91(s, 1H), 12.1(br, 1H)

FAB (M+H) 227

58-2) 1-(t-Butyl)-3-(naphthalen-1-yl)-1H-pyrazole-4-carboxylic acidethyl ester

6.3 g(28 mmol) of the compound prepared in Preparation 58-1) and 2.44g(30.8 mmol) of ethylpropiolate were dissolved in a solvent mixture of27 ml of acetic acid and 32 ml of acetonitrile, and the whole mixturewas reacted in the air for 3 days. The solvent was removed, and theresidue was subjected to silica gel column chromatography (eluent: ethylacetate/n-hexane=9/1, v/v) to obtain 6.76 g(21 mmol, Yield 75%) of thetitle compound.

¹H NMR(CDCl₃) δ 0.80(t, 3H), 1.65(s, 9H), 3.98(q, 2H), 7.38(m, 2H), 7.48(m, 1H), 7.55(m, 1H), 7.74(m, 1H); 7.85(m, 2H), 8.21(s, 1H), 11.31(br,1H)

FAB (M+H): 323

58-3) 3-(Naphthalen-1-yl)-1H-pyrazole-4-carboxylic acid ethylester

3.65 g(11.3 mmol) of the compound prepared in Preparation 58-2) wasdissolved in 50 ml of formic acid, and the resulting solution was boiledfor 12 hours under reflux. The solvent therein was removed bydistillation under reduced pressure, and ethyl acetate was addedthereto. The mixture was washed with saturated aqueous sodium hydrogencarbonate solution and dried over anhydrous magnesium sulfate. Thesolvent was removed by distillation under reduced pressure, and theresidue was subjected to silica gel column chromatography(eluent: ethylacetate/n-hexane=6/4, v/v) to obtain 1.1 g(4.1 mmol, Yield 37%) of thetitle compound(see, J. Hetero. Chem., 31, 1447, 1944).

¹H NMR(CDCl₃) δ 0.80(t, 3H), 3.98(q, 2H), 7.35-7.60(m, 5H), 7.90(m, 2H),7.94(s, 1H)

FAB (M+H): 267

58-4) 3-(Naphthalen-1-yl)-1H-pyrazole-4-carboxylic acid

1.1 g(4.1 mmol) of the compound prepared in Preparation 58-3) and 2.1g(12.4 mmol) of potassium hydroxide were dissolved in 50 ml of a solventmixture of methanol/water(1:1, v/v). The mixture was reacted underreflux for 12 hours. The solvent was removed by distillation underreduced pressure. The residue was acidified with 1N aqueous hydrochloricacid solution, extracted with 50 ml of ethyl acetate and dried overanhydrous magnesium sulfate. The solvent was removed by distillationunder reduced pressure to obtain 910 mg(3.8 mmol, Yield 92%) of thetitle compound.

¹H NMR(CD₃OD+CDCl₃) δ 7.30(m, 3H), 7.56(d, 1H), 7.80-7.95 (m, 3H), 8.07(s, 1H)

FAB (M+H): 239

58-5)4-[N-(2-Methoxyethyl)-N-methyl]carbamoyl-3-(naphthalen-1-yl)-1H-pyrazole

238 mg(1 mmol) of the compound prepared in Preparation 58-4) wasdissolved in 10 ml of dimethylformamide, and 230 mg(1.2 mmol) of EDC,101 mg(1 mmol) of triethylamine and 162 mg(1.2 mmol) ofHOBT(1-hydroxybenzotriazole) were added thereto, and then the mixturewas stirred at 0° C. for 5 minutes. To the mixture was added 124 mg (1mmol) of N-(2-methoxyethyl)-N-methylamine hydrochloride, which was thenstirred at room temperature for 5 hours. The solvent was removed underreduced pressure, 10 ml of saturated aqueous potassium carbonatesolution was added to the residue. The mixture was extracted with 20 mlof ethyl acetate, washed with 10 ml of 1N aqueous hydrochloric acidsolution, washed with saturated sodium chloride solution and water,dried over anhydrous sodium sulfate, and concentrated to obtain 247mg(0.8 mmol, Yield 80%) of the title compound.

¹H NMR(CDCl₃) δ 2.40(s, 2H), 2.81(s, 1H), 2.84(s, 1H), 2.96(s, 1H), 3.02(s, 4H), 3.15(s, 1.5H), 3.34(s, 1.5H), 7.24-7.52(m, 4H), 7.59(s, 1H),7.77(m, 2H), 7.93(d, 1H)

FAB (M+H): 310

Preparation 59 Synthesis of4-(Morpholin-4-yl)carbonyl-3-(naphthalen-1-yl)-1H-pyrazole

238 mg(1 mmol) of the compound prepared in Preparation 58-4) wasdissolved in 10 ml of dimethylformamide, and 230 mg(1.2 mmol) of EDC and162 mg(1.2 mmol) of HOBT were added thereto, and the mixture was stirredat 0° C. for 5 minutes. To the whole mixture was added 87 mg(1 mmol) ofmorpholine, which was then stirred at room temperature for 5 hours. Thesolvent was removed under reduced pressure and 10 ml of saturatedaqueous potassium carbonate solution was added to the residue. Themixture was extracted with 20 ml of ethyl acetate, washed with 10 ml of1N hydrochloric acid solution, washed with saturated aqueous sodiumchloride solution and water, dried over anhydrous sodium sulfate, andconcentrated to obtain 240 mg(0.8 mmol, Yield 80%) of the titlecompound.

¹H NMR(CDCl₃) δ 2.5(br, 2H), 2.95(br, 2H), 3.15(br, 2H), 3.40(br, 2H),7.50 (m, 4H), 7.95(m, 4H), 9.73(br, 1H)

FAB (M+H): 308

EXAMPLE 152 Synthesis of1-[1-(1-Benzyloxycarbonyl-piperidin-4-ylmethyl)-1H-imidazol-5-ylmethyl]-4[N-(2-methoxyethyl)-N-methyl]carbamoyl-3-(naphthalen-1-yl)-1H-pyrazole(152)

616 mg(2.0 mmol) of the compound prepared in Preparation 56-4) wasdissolved in 10 ml of dimethylformamide, 264 mg(6.6 mmol) of sodiumhydride(60%) was added thereto at 0° C., and the whole mixture wasstirred for 5 minutes. To the mixture was added 765 mg(2.2 mmol) of thecompound prepared in Preparation 58-5) and the resulting mixture wasstirred at room temperature for 5 hours. The solvent was removed bydistillation under reduced pressure, and 10 ml of water was added to theresidue. The mixture was then extracted twice with 20 of ethyl acetate,dried over magnesium sulfate, concentrated, and subjected to silica gelcolumn chromatography(eluent: dichloromethane/methanol=90/10, v/v) toobtain 930 mg(Yield 75%) of the title compound.

¹H NMR(CDCl₃) δ 1.11(m, 2H), 1.37(br, 1H), 1.50(br, 2H), 2.35(br, 1H),2.55 (br, 2H), 2.71(br, 1H), 2.90-3.21(m, 7H), 3.35(br, 1H), 3.90(br,2H), 3.98(d, 1H), 4.50(d, 1H), 5.02(s, 2H), 5.10(s, 2H), 7.21-7.40(m,6H), 7.41-7.60(m, 4H), 7.70 (s, 1H), 7.80(s, 1H), 7.95(m, 2H), 8.13(d,1H)

FAB (M+H): 621

EXAMPLE 153 Synthesis of1-[1-(1-Methoxycarbonylpiperidin-4-ylmethyl)-1H-imidazole-5-ylmethyl]-4-[N-(2-methoxyethyl)-N-methyl]carbamoyl-3-(naphthalen-1-yl)-1H-pyrazole(153)

153-1)1-1-(Piperidin-4-ylmethyl)-1H-imidazole-5-ylmethyl]4-[N-(2-methoxyethyl)-N-methyl]carbamoyl-3-(naphthalen-1-yl)-1H-pyrazole

227 mg(0.36 mmol) of the compound prepared in Example 152 was dissolvedin methanol, 20 mg of palladium hydroxide carbon was added thereto, andthen the mixture was reacted under 1 atm of hydrogen for 2 hours. Afterthe reaction was completed, the mixture was filtered and the solvent wasremoved. The filtrate was subjected to silica gel columnchromatography(eluent: ammonia water/methanol=15/85, v/v) to obtain 128mg(0.26 mmol, Yield 74%) of the title compound.

¹H NMR(CDCl₃) δ 1.08(s, 2H), 1.53(m, 4H), 2.33(s, 2H), 2.64(br, 4H),3.20(m, 6H), 3.31(s, 1H), 3.75(d, 2H), 4.13(m, 2H), 5.10(s, 2H), 6.71(s,1H), 7.11(s, 1H), 7.30(m, 9H), 7.74(d, 1H), 7.81(d, 1H), 7.90(s, 1H),8.06(d, 1H)

FAB (M+H): 486

153-2)1-[1-(1-methoxycarbonylpiperidin-4-ylmethyl)-1H-imidazol-5-ylmethyl]-4-[N-(2-methoxyethyl)-N-methyl]carbamoyl-3-(naphthalen-1-yl)-1H-pyrazole

30 mg(62 μmol) of the compound prepared in Example 153-1) was added to 2ml of dichloromethane, 5.4 mg(6.9 μmol) of methylchloroformate was addedthereto by an injector, and the mixture was stirred for 2 hours. Thesolvent was removed under reduced pressure, and the residue wassubjected to silica gel column chromatography(eluent:dichloromethane/methanol=80/20, v/v) to obtain 27.8 mg(5.3 μmol, Yield85%) of the title compound.

¹H NMR(CDCl₃) δ 1.11(br, 2H), 1.33(br, 1H), 1.53(br, 2H), 2.39(s, 2H),2.70 (br, 4H), 2.90-3.20(br, 6H), 3.32(s, 1H), 3.62(s, 3H), 3.78(d, 2H),4.16(m, 2H), 5.16(s, 2H), 6.74(s, 1H), 7.10(s, 1H), 7.21-7.50(m, 14H),7.76(d, 1H), 7.84(d, 1H), 7.91(s, 1H), 8.07(d, 1H)

FAB (M+H): 545

EXAMPLE 154 Synthesis of1-[1-(4-Bromobenzyl)-1H-imidazol-5-ylmethyl]-4-[N-(2-methoxyethyl)-N-methyl]carbamoyl-3-(naphthalen-1-yl)-1H-pyrazole(154)

The title compound was obtained in a yield 81% according to the sameprocedure as Example 152 except that the compound prepared inPreparation 32-2) and the compound prepared in Preparation 58-5) wereused.

¹H NMR(CDCl₃) δ 2.41(s, 2H), 2.82(s, 1H), 2.85(s, 1H), 2.98(s, 1H),3.04(s, 4H), 3.17(s, 1.5H), 3.36(s, 1.5H), 5.11(s, 2H), 5.21(s, 2H),6.95(d, 2H), 7.25(d, 2H), 7.35-7.60(m, 5H), 7.64(s, 1H), 7.72(s, 1H),7.81(m, 2H), 8.11 (d, 1H)

FAB (M+H): 558

EXAMPLE 155 Synthesis of1-[1-(4-Chlorobenzyl)-1H-imidazol-5-ylmethyl]-4-[N-(2-methoxyethyl)-N-methyl]carbamoyl-3-(naphthalen-1-yl)-1H-pyrazole(155)

The title compound was obtained in a yield 81% according to the sameprocedure as Example 152 except that the compound prepared inPreparation 57-2) and the compound prepared in Preparation 58-5) wereused.

¹H NMR(CDCl₃) δ 2.41(s, 2H), 2.82(s, 1H), 2.85(s, 1H), 2.98(s, 1H), 3.04(s, 4H), 3.17(s, 1.5H), 3.36(s, 1.5H), 5.20(s, 2H), 5.25(s, 2H), 6.97(d,2H), 7.26(d, 2H), 7.35-7.46(m, 5H), 7.47(s, 1H), 7.58(s, 1H), 7.88(m,2H), 8.11(d, 1H)

FAB (M+H): 514

EXAMPLE 156 Synthesis of1-[1-(4-Cyanobenzyl)-1H-imidazol-5-ylmethyl-1-4-[N-(2-methoxyethyl)-N-methyl]carbamoyl-3-(naphthalen-1-yl)-1H-pyrazole(156)

The title compound was obtained in a yield 81% according to the sameprocedure as Example 152 except that the compound prepared inPreparation 29-5) and the compound prepared in Preparation 58-5) wereused.

¹H H NMR(CDCl₃) δ 2.41(s, 2H), 2.82(s, 1H), 2.85(s, 1H), 2.98(s, 1H),3.04 (s, 4H), 3.17(s, 1.5H), 3.36(s, 1.5H), 5.20(s, 2H), 5.31(s, 2H),6.99(d, 2H), 7.26 (d, 2H), 7.35-7.46(m, 5H), 7.48(s, 1H), 7.57(s, 1H),7.89(m, 2H), 8.12(d, 1H)

FAB (M+H): 505

EXAMPLE 157 Synthesis of1-[1-Methyl-1H-imidazol-5-ylmethyl-7-4-[N-(2-methoxyethyl)-N-methyl]carbamoyl-3-(naphthalen-1-yl)-1H-pyrazole(157)

The title compound was obtained in a yield 81% according to the sameprocedure as Example 152 except that1-methyl-5-chloromethyl-1H-imidazole hydrochloride and the compoundprepared in Preparation 58-5) were used.

¹H NMR(CDCl₃) δ 2.42(br, 2H), 2.71(br, 1H), 3.10(br, 5H), 3.30(br, 1H),3.50(s, 3H), 5.17(s, 2H), 6.69(s, 1H), 7.09(s, 1H), 7.41(m, 9H), 7.74(d,1H), 7.83 (d, 1H), 7.89(s, 1H), 8.05(d, 1H)

FAB (M+H): 404

EXAMPLE 158 Synthesis of1-[1-(1-Benzyloxycarbonyl-piperidin-4-ylmethyl)-1H-imidazol-5-ylmethyl]-4-(morpholin-4-yl)carbonyl-3-(naphthalen-1-yl)-1H-pyrazole(158)

612 mg(2.0 mmol) of the compound prepared in Preparation 59 wasdissolved in 10 ml of dimethylformamide, 264 mg(6.6 mmol) of sodiumhydride(60%) was added thereto at 0° C., and the whole mixture wasstirred for 5 minutes. To the mixture was added 765 mg(2.2 mmol) of thecompound prepared in Preparation 56-4), which was then stirred at roomtemperature for 5 hours. The solvent was removed by distillation underreduced pressure and 10 ml of water was added to the residue. Theresulting mixture was then extracted twice with 20 ml of ethyl acetate,dried over magnesium sulfate, concentrated, and subjected to silica gelcolumn chromatography(eluent: dichloromethane/methanol=90/10, v/v) toobtain 930 mg(Yield 75%) of the title compound.

¹H NMR(CDCl₃) δ 1.11(m, 2H), 1.37(br, 1H), 1.50(br, 2H), 1.62(br, 1H),2.35(br, 1H), 2.55(br, 2H), 2.71(br, 1H), 3.14(br, 2H) 3.35(br, 2H),3.90(br, 2H), 4.15(m, 4H), 5.02(s, 2H), 5.10(s, 2H), 7.21-7.40(m, 6H),7.41-7.60(m, 4H), 7.70 (s, 1H), 7.80(s, 1H), 7.95(m, 2H), 8.13(d, 1H)

FAB (M+H); 619

EXAMPLE 159 Synthesis of1-[1-(1-Methoxycarbonylpiperidin-4-ylmethyl)-1H-imidazol-5-ylmethyl]-4-(morpholin-4-yl)carbonyl-3-(naphthalen-1-yl)-1H-pyrazole(159)

159-1)1-[1-(Piperidin-4-ylmethyl)-1H-imidazol-5-ylmethyl]4-(morpholin-4-yl)carbonyl-3-(naphthalen-1-yl)-1H-pyrazole

227 mg(0.36 mmol) of the compound prepared in Example 158 was dissolvedin methanol, 20 mg of palladium hydroxide carbon was added thereto, andthe mixture was reacted under 1 atm of hydrogen for 2 hours. After thereaction was completed, the mixture was filtered and the solvent thereinwas removed. The residue was subjected to silica gel columnchromatography(eluent: ammonia water/methanol=15/85, v/v) to give 120mg(0.26 mmol, Yield 74%) of the title compound.

¹H NMR(CDCl₃) δ 1.06(m, 2H), 1.43(m, 3H), 2.36(br, 5H), 2.41-3.79(br,13H), 3.78(d, 2H), 5.22(s, 2H), 6.88(s, 1H), 7.12(d, 2H), 7.26(m, 1H),7.35(m, 3H), 7.63(s, 1H), 7.75(d, 1H), 7.80(d, 1H), 7.93(d, 1H)

FAB (M+H): 484

159-2)1-[1-(1-Methoxycarbonylpiperidin-4-ylmethyl)-1H-imidazol-5-ylmethyl]-4-(morpholin-4-yl)carbonyl-3-(naphthalen-1-yl)-1H-pyrazole

30 mg(62 μmol) of the compound prepared in Example 159-1) was dissolvedin 2 ml of dichloromethane, 5.4 mg(6.9 μmol) of methylchloroformate wasadded thereto by injector, and the whole mixture was stirred for 2hours. The solvent was removed under reduced pressure, and the residuewas subjected to silica gel column chromatography(eluent:dichloromethane/methanol=80/20, v/v) to give 27.8 mg(5.3 μmol, Yield85%) of the title compound.

¹H NMR(CDCl₃) δ 1.05(br, 2H), 1.32(br, 1H), 1.53(br, 2H), 2.31-2.72(m,5H), 3.03˜3.33(m, 7H), 3.62(s, 3H), 3.66(m, 2H), 4.13(br, 2H), 5.12(s,2H), 6.71 (s, 1H), 7.03(s, 1H), 7.14(s, 1H), 7.24˜7.43(m, 5H), 7.74(d,1H), 7.82(d, 1H), 8.10(d, 1H)

FAB (M+H): 543

EXAMPLE 160 Synthesis of1-[1-(4-Bromobenzyl)-1H-imidazol-5-ylmethyl]-4-(morpholin-4-yl)carbonyl-3-(naphthalen-1-yl)-1H-pyrazole(160)

The title compound was obtained in a yield 81% according to the sameprocedure as Example 152 except that the compound prepared inPreparation 32-2) and the compound prepared in Preparation 59 were used.

¹H NMR(CDCl₃) δ 2.35(br, 2H), 2.80(br, 2H), 3.15(br, 2H), 3.35(br, 2H),5.29(s, 2H), 5.31 (s, 2H), 7.00(d, 2H), 7.20-7.35(m, 3H), 7.40-7.60(m,4H), 7.72 (s, 1H), 7.80(s, 1H), 7.90(m, 2H), 8.01(d, 1H)

FAB (M+H): 556

EXAMPLE 161 Synthesis of1-[1-(4-chlorobenzyl)-1H-imidazol-5-ylmethyl]-4-(morpholin-4-yl)carbonyl-3-(naphthalen-1-yl)-1H-pyrazole(161)

The title compound was obtained in a yield 81% according to the sameprocedure as Example 152 except that the compound prepared inPreparation 57-2) and the compound prepared in Preparation 59 were used.

¹H NMR(CDCl₃) δ 2.35(br, 2H), 2.80(br, 2H), 3.15(br, 2H), 3.35(br, 2H),5.29(s, 2H), 5.31(s, 2H), 7.00(d, 2H), 7.20-7.35(m, 3H), 7.40-7.60(m,4H), 7.72 (s, 1H), 7.80(s, 1H), 7.90(m, 2H), 8.01(d, 1H)

FAB (M+H): 512

EXAMPLE 162 Synthesis of1-[1-(4-Cyanobenzyl)-1H-imidazol-5-ylmethyl]-4-(morpholin-4-yl)carbonyl-3-(naphthalen-1-yl)-1H-pyrazole(162)

The title compound was obtained in a yield 81% according to the sameprocedure as Example 152 except that the compound prepared inPreparation 29-5) and the compound prepared in Preparation 59 were used.

¹H NMR(CDCl₃) δ 2.35(br, 2H), 2.80(br, 2H), 3.15(br, 2H), 3.35(br, 2H),5.28(s, 2H), 5.34(s, 2H), 7.03(d, 2H), 7.20-7.35(m, 3H), 7.40-7.60(m,4H), 7.72 (s, 1H), 7.80(s, 1H), 7.90(m, 2H), 8.01(d, 1H)

FAB (M+H): 503

EXAMPLE 163 Synthesis of1-(1-Methyl-1H-imidazol-5-ylmethyl)-4-(morpholin-4-yl)carbonyl-3-(naphthalen-1-yl)-1H-pyrazole(163)

The title compound was obtained in a yield 81% according to the sameprocedure as Example 152 except that1-methyl-5-chloromethyl-1H-imidazole hydrochloride and the compoundprepared in Preparation 59 were used.

¹H NMR(CDCl₃) δ 2.35(br, 2H), 2.80(br, 2H), 3.15(br, 2H), 3.35(br, 2H),3.62(s, 3H), 5.29(s, 2H), 7.20-7.35(m, 3H), 7.40-7.60(m, 2H), 7.72(s,1H), 7.80 (s, 1H), 7.90(m, 2H), 8.01(d, 1H)

FAB (M+H): 402

EXPERIMENTAL EXAMPLE 1 Analysis of In Vitro Inhibitory Activity for RasFarnesyl Transferase

In the present experiment, Ras farnesyl transferase produced by geneticrecombination techniques according to the improved Pompliano's method(Pompliano et al., Biochemistry, 1992, 31, 3800) was used, and Rassubstrate(Ras-CVLS) protein described in Korean Patent Appln. No.97-14409 was used after it has been purified according to the knownmethod (see, Chung et al, Biochimica et Biophysica Acta, 1992, 278,1129).

The enzyme reaction was performed in 50 μl of 50 mM Sodium HEPES buffersolution containing 25 mM of potassium chloride, 25 mM of magnesiumchloride, 10 mM of DTT and 50 μM of zinc chloride. 1.5 μM of Rassubstrate protein, 0.15 μM of tritium-farnesylpyrophosphate and 4.5 nMof farnesyl transferase were used.

More specifically, in the initial step, farnesyl transferase was addedto the above buffer solution, reaction was maintained for 30 minutes at37° C. and then the reaction was stopped by adding 1 ml of ethanolsolution containing 1M HCl. The formed precipitates were adsorbed toGF/B filter using Hopper harvestor(Hopper #FH 225V) for filter-binding,washed with ethanol, and then radioactivity of the dried filter wasmeasured using LKB β counter. Enzyme titer was measured in theunsaturated state of substrate where the concentrations of Ras substrateprotein and farnesyl transferase have quantitative relationship. Thecompound according to the present invention dissolved in dimethylsulfoxide(DMSO) was added to the reaction solution in an amount of lessthan 5% of the total reaction solution, and then the enzyme inhibitoryactivity thereof was measured. The enzyme inhibitory activity wasrepresented by percentage of the amount of farnesyl incorporated intothe Ras substrate protein in the presence of the test compound to thatin the absence of the test compound. IC₅₀ of the test compound wasdefined as the concentration at which 50% of the enzyme activity wasinhibited.

To evaluate the selective enzyme inhibitory activity of the compoundaccording to the present invention, inhibitory activity ongeranylgeranyl transferase was measured. Geranylgeranyl transferase waspurified from bovine brain according to the method modified fromSchaber's method (Schaber et al., J. Biol. Chem. 1990, 265, 14701), andsubstantially the same experimental procedure as that for farnesyltransferase was performed on geranylgeranyl pyrophosphate and Ras-CVILsubstrate protein.

The test results are represented in the following Table 7.

EXPERIMENTAL EXAMPLE 2 Analysis of In Vivo Inhibitory Activity for RasFarnesyl Transferase

In the present experiment, Rat2 cell line which expresses C-Harvey-Rasprotein having transforming activity and Rat2 cell line (Korean patentapplication No. 97-14409) which is transformed with fused protein ofH-Ras substituted with polybasic lysine domain at C-terminus of K-Raswere used. The experiment was performed by the modified Declue's method(Declue. J. E. et al., Cancer Research, 1991, 51, 712). Hereinafter, theexperimental method will be described in more detail.

3×10⁵ cells of transformed Rat2 fibroblast cell line were sprayed on 60mm cell cultivation dish and cultivated for 48 hours in a cell incubatorat 37° C. and after 50% or more of density was reached, it was treatedwith the test compounds. The compound according to the present inventiondissolved in dimethylsulfoxide(DMSO) was used. 1% concentration ofdimethylsulfoxide was used in both control and test groups. After 4hours from the treatment with the compound, methionine labeled with 150μCi of radioactive isotope [³⁵S] per 1 ml of medium was added and aftercultivating for 20 hours, the cells were washed with physiologicalsaline water. The cells were lysed using 1 ml of cold cell lysis buffersolution(50 mM of Sodium HEPES buffer solution containing 5 mM ofmagnesium chloride, 1 mM of DTT, 1% NP 40, 1 mM of EDTA, 1 mM of PMSF, 2μM of leupeptin, 2 μM of pepstatin A and 2 μM of antipain) and thesupernatant wherein the cells were lysed was obtained by high-velocitycentrifugation of 12,000×5 minutes. The amount of radioisotope in thesupernatant was measured and standardized to obtain a quantitativeresult in immunoprecipitation reaction and then, Y13-259, a monoclonalantibody specifically binding to Ras protein (Furth, M. E. et al., J.Virol, 1982, 43, 294) was added and reacted for 15 hours at 4° C.Protein A (combined with goat anti-murine imunoglobulinantibody)-agarose suspension was added to the solution and reacted for 1hour at 4° C. and then, to remove the unspecific binding product,immunoprecipitates were washed with a buffer solution (50 mM Trischloride buffer solution containing 50 mM of sodium chloride, 0.5% ofsodium dioxycolate, 0.5% of NP 40 and 0.1% of SDS). The precipitateswere added to a buffer solution for electrophoresis and boiled and then,electrophoresis was performed using 13.5% of SDS polyacrylamide gel.After electrophoresis, the gel was fixed and dried. Then, the gel wasexposed to X-ray film, developed and printed. From the result of theexperiment, intensities of band of protein combined with or withoutfarnesyl of Ras protein were measured, and the concentration of the testcompound inhibiting 50% of farnesyl binding was defined as CIC₅₀, an invivo Ras farnesyl transferase inhibitory activity. The test results areshown in the following Table 7.

TABLE 7 COM. H-Ras H-Ras K-Ras K-Ras NO. IC₅₀(μM) CIC₅₀(μM) IC₅₀(μM)CIC₅₀(μM) 1 0.0011 0.025 0.0035 10 2 0.00085 0.025 0.002 10-50 3 0.0010.025 0.0024 15 4 0.047 0.1-1   0.75  10-100 5 0.0037 0.025 0.0085 10-506 0.001 0.025 0.002 10-50 7 0.0006 0.025 0.0022 10-50 8 0.004 0.0250.008 10-50 9 0.005 0.025 0.0066 10-50 10 0.00085 0.0125 0.005 10-50 110.004 0.025 0.008 10-50 12 0.005 0.025 0.0066 10-50 13 0.00085 0.01250.005 10-50 14 0.002 0.0125 0.005 10-50 15 0.005 0.025 0.01 10-50 160.0012 0.0125 0.005 10-50 17 0.002 0.025 0.003 10-50 18 0.001 0.0250.002 10-50 19 0.001 0.020 0.003 10-50 20 0.001 0.020 0.002 10-50 210.001 0.021 0.001 10-50 22 0.001 0.020 0.002 10-50 23 0.002 0.023 0.00210-50 24 0.002 0.025 0.003 10-50 25 0.002 0.015 0.005 10-50 26 0.0020.015 0.003 10-50 27 0.006 0.025 0.005 10-30 28 0.001 0.020 0.002 10-3029 0.002 0.010 0.004 10-20 30 0.002 0.010 0.004 10-20 31 0.002 0.0120.005 10-20 32 0.002 0.015 0.003 10-50 33 0.002 0.018 0.003 10-50 340.002 0.020 0.003 10-50 35 0.001 0.025 0.002 10-50 36 0.001 0.025 0.00210-50 37 0.002 0.025 0.003 10-50 38 0.002 0.025 0.004 10-50 39 0.0020.020 0.003 10-50 40 0.002 0.025 0.003 10-50 41 0.003 0.015 0.004 10-5042 0.004 0.015 0.003 10-50 43 0.001 0.015 0.002  5-10 44 0.25 1-500.1-10  10-100 45 0.13 1-50 0.1-10  10-100 46 0.12 1-50 0.1-10  10-10047 0.09 1-50 0.1-10  10-100 48 0.15 1-50 10  10-100 49 0.03 0.7 0.485<20 50 0.15 1-50 0.1-10  10-100 51 0.27 1-50 0.1-10  10-100 52 0.07 1-500.1-10  10-100 53 0.3 1-50 0.1-10  10-100 54 0.39 1-50 0.1-10  10-100 550.06 1-50 0.1-10  10-100 56 0.04 1-50 0.1-10  10-100 57 0.038 1-500.1-10  10-100 58 0.025 1-50 0.1-10  10-100 59 0.57 1-50 0.1-10  10-10060 0.2 1-50 0.1-10  10-100 61 0.74 1-50 0.1-10  10-100 62 0.068 1-500.1-10  10-100 63 0.23 1-50 0.1-10  10-100 64 0.16 1-50 0.1-10  10-10065 0.42 1-50 0.1-10  10-100 66 0.12 1-50 0.1-10  10-100 67 0.02 30.1-10 >50 68 0.12 1-50 0.1-10  10-100 69 0.55 1-50 0.1-10  10-100 700.21 1-50 0.1-10  10-100 71 0.12 1-50 0.1-10  10-100 72 0.05 1-50 0.1-10 10-100 73 0.002 0.2 0.02 >10 74 0.01 0.1-1   0.01-0.1   10-100 75 0.0050.2 0.16 20 76 0.004 0.1-1   0.1-10  10-100 77 0.004 0.1 0.12 20 780.0045 0.1 0.2  10-100 79 0.005 0.1 0.1 >50 80 8.21 1-50 0.1-10  10-10081 0.68 1-50 0.1-10  10-100 82 0.4 1-50 0.1-10  10-100 83 0.26 1-50 18.5 10-100 84 0.72 1-50 1.83  10-100 85 0.03 4 0.1-10 >50 86 0.03 20.1-10 >50 87 0.06 1-50 0.1-10  10-100 88 0.6 1-50 0.1-10  10-100 890.014 1 0.1-10  10-100 90 0.0425 1-50 0.1-10  10-100 91 2.15 1-50 0.1-10 10-100 92 0.07 1-50 0.1-10  10-100 93 0.32 1-50 0.1-10  10-100 94 0.21-50 0.1-10  10-100 95 0.0007 0.01-0.1  0.1-1  10-50 96 0.23 1-50   1-10 10-100 97 12 10-100   10-100  10-100 98 0.90-0.9 1-50 0.1-10  10-100 990.0030 0.1 0.1 >50 100 1.8 >1 0.1-10 >20 101 0.01 >5 0.8 >50 102 0.451-50 22 >50 103 0.064 0.1-10   1.7  10-100 104 0.0005 <0.05 0.006 <10105 0.0004 0.05 0.09 >50 106 0.9 1-50  10-100  10-100 107 10 1-50 0.1-10 10-100 108 0.26 1-50 0.1-10  10-100 109 8.6 1-50  1-50  10-100 1100.0006 0.008 0.0015 10 111 0.002 0.03 0.002 4 112 0.004 0.015 0.006 10113 0.004 <0.1 <0.1  10-100 114 0.001 0.015 0.100 <100 115 0.002 0.0250.035 <50 116 0.004 0.030 0.062 <50 117 — — — <50 118 — — — <40 119 — —— <30 120 — — — <20 121 — — — <40 122 — — — <30 123 — — — <40 124 — — —<20 125 0.002 0.006 0.004 4 126 0.001 0.012 0.004 5 127 0.002 0.0150.005 5 128 0.002 0.010 0.010 5 129 0.003 0.025 0.004 10-50 130 0.0020.025 0.003 10-50 131 0.001 0.0125 0.0023 10-50 132 0.0035 0.025 0.01110-50 133 0.00065 0.025 0.002 10-50 134 0.0027 0.025 0.002 10-50 1350.0024 0.03 0.004 10-50 136 0.0016 0.025 0.0024 10-50 137 0.0017 0.0200.0021 10-20 138 0.0014 0.025 0.0035 10-50 139 0.005 0.07 37 7 140 0.091-10  10-50 10-50 141 0.23 1-10   10-100 10-50 142 12 >50 >50 >50 1431.2 20 >50 >50 144 0.38 5 50 >50 145 0.007 0.1 0.07 25 146 0.09 1 10 50147 0.002 0.05 0.03 10 148 1.7 30 >50 >50 149 5 50 >50 >50 1508 >50 >50 >50 151 4.6 50 >50 >50 152 0.023 0.1 0.07 10 153 0.03 0.15 0.120 154 0.03 0.15 0.2 10 155 0.02 0.1 0.2 15 156 0.02 0.1 0.2 40 157 0.010.1 5 >50 158 0.25 1 2 30 159 0.3 1.2 4 50 160 0.3 1.5 3 40 161 0.2 1 250 162 0.25 1 2 50 163 0.15 1 10 >50

What is claimed is:
 1. A compound represented by the following formula(3):

wherein X represents O or S, B represents hydrogen, or lower alkyl whichmay be optionally substituted by hydroxy, mercapto, lower alkoxy, loweralkylthio or aryl, C represents hydrogen, or lower alkyl which may beoptionally substituted by aryl; or represents a radical selected fromthe following group:

wherein R₁₁ and R₁₂ independently represent hydrogen, lower alkyl, loweralkoxy, halogen, cyano, hydroxycarbonyl, aminocarbonyl,aminothiocarbonyl, hydroxy, phenyl or phenoxy,

R₁₃ and R₁₄ independently represent hydrogen, lower alkyl, aryl orwherein X is O or S, n₄ is an integer of 2 to 4 and R₁₅ is lower alkyl,D represents a radical selected from the following group:

wherein R₁₀ represents hydrogen, lower alkyl or lower alkoxy, Qrepresents O, S, S═O or SO₂, Z represents O, S, S═O, SO₂, C═O or C═S, orrepresents CH—R₂₀ or N—R₂₀ (wherein R₂₀ is hydrogen, lower alkyl orhydroxy), n₅ denotes an integer of 1 to 3, and R₁₈ and R₁₉ independentlyrepresent hydrogen, halogen, hydroxy, cyano, lower alkyl, lower alkoxy,alkoxyalkyl, alkylthio, hydroxycarbonyl, aminocarbonyl,aminothiocarbonyl, alkylsulfonyl, alkylthioalkyl, alkylthioalkyloxy,aryl; or oxy, thio, sulfonyl or lower alkyl substituted by aryl.